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  <doc>
    <id>6216</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2017-03-03</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Set-free Markov State Building</title>
    <abstract language="eng">Molecular dynamics (MD) simulations face challenging problems since&#13;
the timescales of interest often are much longer than what is possible&#13;
to simulate and even if sufficiently long simulation are possible the complex&#13;
nature of the resulting simulation data makes interpretation difficult.&#13;
Markov State Models (MSMs) help to overcome these problems by making&#13;
experimentally relevant timescales accessible via coarse grained representations&#13;
that also allows for convenient interpretation. However, standard&#13;
set-based MSMs exhibit some caveats limiting their approximation quality&#13;
and statistical significance. One of the main caveats results from the fact&#13;
that typical MD trajectories repeatedly re-cross the boundary between&#13;
the sets used to build the MSM which causes statistical bias in estimating&#13;
the transition probabilities between these sets. In this article, we present&#13;
a set-free approach to MSM building utilizing smooth overlapping ansatz&#13;
functions instead of sets and an adaptive refinement approach. This kind&#13;
of meshless discretization helps to overcome the recrossing problem and&#13;
yields an adaptive refinement procedure that allows to improve the quality&#13;
of the model while exploring state space and inserting new ansatz&#13;
functions into the MSM.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-62167</identifier>
    <identifier type="doi">10.1063/1.4978501</identifier>
    <enrichment key="SourceTitle">Appeared in: Journal of Chemical Physics 146/12 (2017)</enrichment>
    <author>Marcus Weber</author>
    <submitter>Julia Boltze</submitter>
    <author>Konstantin Fackeldey</author>
    <author>Christof Schütte</author>
    <series>
      <title>ZIB-Report</title>
      <number>17-10</number>
    </series>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="fackeldey">Fackeldey, Konstantin</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/6216/ZR-17-10.pdf</file>
  </doc>
  <doc>
    <id>6177</id>
    <completedYear/>
    <publishedYear>2017</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>1</pageFirst>
    <pageLast>52</pageLast>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Importance sampling in path space for diffusion processes with slow-fast variables</title>
    <abstract language="eng">Importance sampling is a widely used technique to reduce the variance of a Monte Carlo estimator by an appropriate change of measure. In this work, we study importance sampling in the framework of diffusion process and consider the change of measure which is realized by adding a control force to the original dynamics. For certain exponential type expectation, the corresponding control force of the optimal change of measure leads to a zero-variance estimator and is related to the solution of a Hamilton–Jacobi–Bellmann equation. We focus on certain diffusions with both slow and fast variables, and the main result is that we obtain an upper bound of the relative error for the importance sampling estimators with control obtained from the limiting dynamics. We demonstrate our approximation strategy with an illustrative numerical example.</abstract>
    <parentTitle language="eng">Probability Theory and Related Fields</parentTitle>
    <identifier type="doi">10.1007/s00440-017-0755-3</identifier>
    <identifier type="url">http://rdcu.be/oA51</identifier>
    <note>If you are not subscribing to the journal please use the http link below as part of the Springer Nature SharedIt initiative</note>
    <enrichment key="PeerReviewed">yes</enrichment>
    <author>Carsten Hartmann</author>
    <submitter>Regine Kossick</submitter>
    <author>Christof Schütte</author>
    <author>Marcus Weber</author>
    <author>Wei Zhang</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
  </doc>
  <doc>
    <id>2289</id>
    <completedYear>2010</completedYear>
    <publishedYear>2010</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>031114</pageFirst>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>3</issue>
    <volume>82</volume>
    <type>article</type>
    <publisherName>American Physical Society</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Observation uncertainty in reversible Markov chains</title>
    <parentTitle language="eng">Phys. Rev. E</parentTitle>
    <identifier type="doi">10.1103/PhysRevE.82.031114</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <author>Ph. Metzner</author>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
  </doc>
  <doc>
    <id>7843</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2020-06-03</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">How to calculate pH-dependent binding rates for receptor-ligand systems based on thermodynamic simulations with different binding motifs</title>
    <abstract language="eng">Molecular simulations of ligand-receptor interactions are a computational challenge, especially when their association- (``on''-rate) and dissociation- (``off''-rate) mechanisms are working on vastly differing timescales. In addition, the timescale of the simulations themselves is, in practice, orders of magnitudes smaller than that of the mechanisms; which further adds to the complexity of observing these mechanisms, and of drawing meaningful and significant biological insights from the simulation.  &#13;
&#13;
&#13;
One way of tackling this multiscale problem is to compute the free-energy landscapes, where molecular dynamics (MD) trajectories are used to only produce certain statistical ensembles. The approach allows for deriving the transition rates between energy states as a function of the height of the activation-energy barriers. In this article, we derive the association rates of the opioids fentanyl and N-(3-fluoro-1-phenethylpiperidin-4-yl)- N-phenyl propionamide (NFEPP) in a $\mu$-opioid receptor by combining the free-energy landscape approach with the square-root-approximation method (SQRA), which is a particularly robust version of Markov modelling. The novelty of this work is that we derive the association rates as a function of the pH level using only an ensemble of MD simulations. We also verify our MD-derived insights by reproducing the in vitro study performed by the Stein Lab, who investigated the influence of pH on the inhibitory constant of fentanyl and NFEPP (Spahn et al. 2017). &#13;
&#13;
MD simulations are far more accessible and cost-effective than in vitro and in vivo studies. Especially in the context of the current opioid crisis, MD simulations can aid in unravelling molecular functionality and assist in clinical decision-making; the approaches presented in this paper are a pertinent step forward in this direction.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="doi">10.1080/08927022.2020.1839660</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-78437</identifier>
    <enrichment key="SourceTitle">Molecular Simulation, 46:18, 1443-1452</enrichment>
    <submitter>Vikram Sunkara</submitter>
    <author>Sourav Ray</author>
    <author>Vikram Sunkara</author>
    <author>Christof Schütte</author>
    <author>Marcus Weber</author>
    <series>
      <title>ZIB-Report</title>
      <number>20-18</number>
    </series>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Opioid, Ligand-Receptor Interaction, Binding Kinetics, Molecular Dynamics, Metadynamics, SQRA</value>
    </subject>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="persons" number="sunkara">Sunkara, Vikram</collection>
    <collection role="projects" number="MathPlusAA1-1">MathPlusAA1-1</collection>
    <collection role="projects" number="MathPlus - AA6">MathPlus - AA6</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/7843/Ray et al_06_2020.pdf</file>
  </doc>
  <doc>
    <id>7939</id>
    <completedYear>2020</completedYear>
    <publishedYear>2020</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>1443</pageFirst>
    <pageLast>1452</pageLast>
    <pageNumber/>
    <edition/>
    <issue>18</issue>
    <volume>46</volume>
    <type>article</type>
    <publisherName>Taylor and Francis</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2020-11-08</completedDate>
    <publishedDate>2020-11-08</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">How to calculate pH-dependent binding rates for receptor-ligand systems based on thermodynamic simulations with different binding motifs</title>
    <abstract language="eng">Molecular simulations of ligand–receptor interactions are a computational challenge, especially when their association- (‘on’-rate) and dissociation- (‘off’-rate) mechanisms are working on vastly differing timescales. One way of tackling this multiscale problem is to compute the free-energy landscapes, where molecular dynamics (MD) trajectories are used to only produce certain statistical ensembles. The approach allows for deriving the transition rates between energy states as a function of the height of the activation-energy barriers. In this article, we derive the association rates of the opioids fentanyl and N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide (NFEPP) in a μ-opioid receptor by combining the free-energy landscape approach with the square-root-approximation method (SQRA), which is a particularly robust version of Markov modelling. The novelty of this work is that we derive the association rates as a function of the pH level using only an ensemble of MD simulations. We also verify our MD-derived insights by reproducing the in vitro study performed by the Stein Lab.</abstract>
    <parentTitle language="deu">Molecular Simulation</parentTitle>
    <identifier type="doi">10.1080/08927022.2020.1839660</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="PreprintUrn">urn:nbn:de:0297-zib-78437</enrichment>
    <author>Sourav Ray</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Vikram Sunkara</author>
    <author>Christof Schütte</author>
    <author>Marcus Weber</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="MODAL-MedLab">MODAL-MedLab</collection>
    <collection role="persons" number="sunkara">Sunkara, Vikram</collection>
    <collection role="projects" number="MODAL-Gesamt">MODAL-Gesamt</collection>
    <collection role="institutes" number="MfLMS">Mathematics for Life and Materials Science</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
  </doc>
  <doc>
    <id>6709</id>
    <completedYear/>
    <publishedYear>2018</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume>7</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Mathematical modeling of the spreading of innovations in the ancient world</title>
    <parentTitle language="eng">eTopoi. Journal for Ancient Studies</parentTitle>
    <identifier type="issn">ISSN 2192-2608</identifier>
    <identifier type="doi">10.17171/4-7-1</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="FulltextUrl">http://journal.topoi.org/index.php/etopoi/index</enrichment>
    <author>Natasa Djurdjevac Conrad</author>
    <submitter>Erlinda Koernig</submitter>
    <author>Daniel Fuerstenau</author>
    <author>Ana Grabundzija</author>
    <author>Luzie Helfmann</author>
    <author>Martin Park</author>
    <author>Wolfram Schier</author>
    <author>Brigitta Schütt</author>
    <author>Christof Schütte</author>
    <author>Marcus Weber</author>
    <author>Niklas Wulkow</author>
    <author>Johannes Zonker</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="persons" number="natasa.conrad">Conrad, Natasa</collection>
    <collection role="projects" number="INNOSPREAD">INNOSPREAD</collection>
  </doc>
  <doc>
    <id>10266</id>
    <completedYear/>
    <publishedYear>2026</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Importance sampling of unbounded random stopping times: computing committor functions and exit rates without reweighting</title>
    <abstract language="eng">Rare events in molecular dynamics are often related to noise-induced transitions between different macroscopic states (e.g., in protein folding). A common feature of these rare transitions is that they happen on timescales that are on average exponentially long compared to the characteristic timescale of the system, with waiting time distributions that have (sub)exponential tails and infinite support. As a result, sampling such rare events can lead to trajectories that can be become arbitrarily long, with not too low probability, which makes the reweighting of such trajectories a real challenge. Here, we discuss rare event simulation by importance sampling from a variational perspective, with a focus on applications in molecular dynamics, in particular the computation of committor functions. The idea is to design importance sampling schemes that (a) reduce the variance of a rare event estimator while controlling the average length of the trajectories and (b) that do not require the reweighting of possibly very long trajectories. In doing so, we study different stochastic control formulations for committor and mean first exit times, which we compare both from a theoretical and a computational point of view, including numerical studies of some benchmark examples.</abstract>
    <identifier type="arxiv">2601.01489</identifier>
    <enrichment key="SubmissionStatus">under review</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">false</enrichment>
    <author>Carsten Hartmann</author>
    <submitter>Alexander Sikorski</submitter>
    <author>Annika Jöster</author>
    <author>Christof Schütte</author>
    <author>Alexander Sikorski</author>
    <author>Marcus Weber</author>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <collection role="persons" number="sikorski">Sikorski, Alexander</collection>
    <collection role="projects" number="SFB-1114-B3">SFB-1114-B3</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
  </doc>
  <doc>
    <id>5573</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2015-08-19</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Finding dominant structures of nonreversible Markov processes</title>
    <abstract language="eng">Finding metastable sets as dominant structures of Markov processes has been shown to be especially useful in modeling interesting slow dynamics of various real world complex processes. Furthermore, coarse graining of such processes based on their dominant structures leads to better understanding and dimension reduction of observed systems. However, in many cases, e.g. for nonreversible Markov processes, dominant structures are often not formed by metastable sets but by important cycles or mixture of both. This paper aims at understanding and identifying these different types of dominant structures for reversible as well as nonreversible ergodic Markov processes. Our algorithmic approach generalizes spectral based methods for reversible process by using Schur decomposition techniques which can tackle also nonreversible cases. We illustrate the mathematical construction of our new approach by numerical experiments.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-55739</identifier>
    <identifier type="doi">10.1137/15M1032272</identifier>
    <enrichment key="SourceTitle">Appeared in: Multiscale Modeling and Simulation 14(4): 1319-1340</enrichment>
    <author>Natasa Djurdjevac Conrad</author>
    <submitter>Erlinda Koernig</submitter>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <series>
      <title>ZIB-Report</title>
      <number>15-40</number>
    </series>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>nonreversible Markov processes</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>metastable sets</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cycle decomposition</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Schur decomposition</value>
    </subject>
    <collection role="msc" number="60J20">Applications of Markov chains and discrete-time Markov processes on general state spaces (social mobility, learning theory, industrial processes, etc.) [See also 90B30, 91D10, 91D35, 91E40]</collection>
    <collection role="msc" number="65C40">Computational Markov chains</collection>
    <collection role="msc" number="82C26">Dynamic and nonequilibrium phase transitions (general)</collection>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="BMS-Nielsen">BMS-Nielsen</collection>
    <collection role="projects" number="EyeTracking">EyeTracking</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="persons" number="natasa.conrad">Conrad, Natasa</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/5573/ZIB-Report_15-40.pdf</file>
  </doc>
  <doc>
    <id>5167</id>
    <completedYear/>
    <publishedYear>2014</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>A2654</pageFirst>
    <pageLast>A2672</pageLast>
    <pageNumber/>
    <edition/>
    <issue>6</issue>
    <volume>36</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Applications of the cross-entropy method to importance sampling and optimal control of diffusions</title>
    <parentTitle language="eng">Siam Journal on Scientific Computing</parentTitle>
    <identifier type="doi">10.1137/14096493X</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="PreprintUrn">urn:nbn:de:0297-zib-49720</enrichment>
    <author>Wei Zhang</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Han Wang</author>
    <author>Carsten Hartmann</author>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="MIP_FORMATION">MIP_FORMATION</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
  </doc>
  <doc>
    <id>5141</id>
    <completedYear/>
    <publishedYear>2015</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>69</pageFirst>
    <pageLast>78</pageLast>
    <pageNumber/>
    <edition/>
    <issue>1</issue>
    <volume>113</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Markov State Models and Molecular Alchemy</title>
    <abstract language="deu">In recent years Markov State Models (MSMs) have attracted a consid-&#13;
erable amount of attention with regard to modelling conformation changes and associated function of biomolecular systems. They have been used successfully, e.g., for peptides including time-resolved spectroscopic experiments, protein function and protein folding , DNA and RNA, and ligand-receptor interaction in drug design and more complicated multivalent scenarios. In this article a novel reweighting scheme is introduced that allows to construct an MSM for certain molecular system out of an MSM for a similar system. This permits studying how molecular properties on long timescales differ between similar molecular systems without performing full molecular dynamics simulations for each system under con-&#13;
sideration. The performance of the reweighting scheme is illustrated for simple test cases including one where the main wells of the respective energy landscapes are located differently and an alchemical transformation of butane to pentane where the dimension of the state space is changed.</abstract>
    <parentTitle language="eng">Molecular Physics</parentTitle>
    <identifier type="doi">10.1080/00268976.2014.944597</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="PreprintUrn">urn:nbn:de:0297-zib-46718</enrichment>
    <author>Christof Schütte</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Adam Nielsen</author>
    <author>Marcus Weber</author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>MSM</value>
    </subject>
    <subject>
      <language>deu</language>
      <type>uncontrolled</type>
      <value>Reweighting</value>
    </subject>
    <subject>
      <language>deu</language>
      <type>uncontrolled</type>
      <value>Girsanov</value>
    </subject>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="BMS-Nielsen">BMS-Nielsen</collection>
    <collection role="projects" number="EyeTracking">EyeTracking</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <collection role="projects" number="TransRisk">TransRisk</collection>
  </doc>
  <doc>
    <id>6262</id>
    <completedYear/>
    <publishedYear>2017</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>12</issue>
    <volume>146</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Set-Free Markov State Model Building</title>
    <parentTitle language="eng">Journal of Chemical Physics</parentTitle>
    <identifier type="doi">10.1063/1.4978501</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="PreprintUrn">urn:nbn:de:0297-zib-62167</enrichment>
    <author>Marcus Weber</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Konstantin Fackeldey</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="fackeldey">Fackeldey, Konstantin</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
  </doc>
  <doc>
    <id>4985</id>
    <completedYear/>
    <publishedYear>2014</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>49</pageFirst>
    <pageLast>65</pageLast>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume>1</volume>
    <type>incollection</type>
    <publisherName>European Mathematical Society</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Design of functional molecules</title>
    <parentTitle language="eng">MATHEON-Mathematics for Key Technologies</parentTitle>
    <enrichment key="Series">Series in Industrial and Applied Mathematics</enrichment>
    <enrichment key="PeerReviewed">no</enrichment>
    <author>Christof Schütte</author>
    <editor>Peter Deuflhard</editor>
    <submitter>Erlinda Körnig</submitter>
    <author>Peter Deuflhard</author>
    <editor>Martin Grötschel</editor>
    <author>Frank Noé</author>
    <editor>Dietmar Hömberg</editor>
    <author>Marcus Weber</author>
    <editor>Ulrich Horst</editor>
    <editor>Jürg Kramer</editor>
    <editor>Volker Mehrmann</editor>
    <editor>Konrad Polthier</editor>
    <editor>Frank Schmidt</editor>
    <editor>Christof Schütte</editor>
    <editor>Martin Skutella</editor>
    <editor>Jürgen Sprekels</editor>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="BMS-Nielsen">BMS-Nielsen</collection>
    <collection role="projects" number="Matheon-A19">Matheon-A19</collection>
  </doc>
  <doc>
    <id>4972</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2014-04-23</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Applications of the cross-entropy method to importance sampling and optimal control of diffusions</title>
    <abstract language="eng">We study the cross-entropy method for diffusions. One of the results is a versatile cross-entropy algorithm that can be used to design efficient importance sampling strategies for rare events or to solve optimal control problems. The approach is based on the minimization of a suitable cross-entropy functional, with a parametric family of exponentially tilted probability distributions. We illustrate the new algorithm with several numerical examples and discuss algorithmic issues and possible extensions of the method.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-49720</identifier>
    <identifier type="doi">10.1137/14096493X</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="SourceTitle">Appeared in: Siam Journal on Scientific Computing 36 (2014) A 2654-A2672</enrichment>
    <author>Wei Zhang</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Han Wang</author>
    <author>Carsten Hartmann</author>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <series>
      <title>ZIB-Report</title>
      <number>14-10</number>
    </series>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>important sampling</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>optimal control</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>cross-entropy method</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>rare events</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>change of measure</value>
    </subject>
    <collection role="msc" number="65C05">Monte Carlo methods</collection>
    <collection role="msc" number="93E20">Optimal stochastic control</collection>
    <collection role="msc" number="94A17">Measures of information, entropy</collection>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/4972/ZIB-Report_14-10.pdf</file>
  </doc>
  <doc>
    <id>4671</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2014-03-05</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Markov State Models and Molecular Alchemy</title>
    <abstract language="deu">In recent years Markov State Models (MSMs) have attracted a consid-&#13;
erable amount of attention with regard to modelling conformation changes&#13;
and associated function of biomolecular systems. They have been used&#13;
successfully, e.g., for peptides including time-resolved spectroscopic ex-&#13;
periments, protein function and protein folding , DNA and RNA, and&#13;
ligand-receptor interaction in drug design and more complicated multi-&#13;
valent scenarios. In this article a novel reweighting scheme is introduced&#13;
that allows to construct an MSM for certain molecular system out of an&#13;
MSM for a similar system. This permits studying how molecular proper-&#13;
ties on long timescales differ between similar molecular systems without&#13;
performing full molecular dynamics simulations for each system under con-&#13;
sideration. The performance of the reweighting scheme is illustrated for&#13;
simple test cases including one where the main wells of the respective en-&#13;
ergy landscapes are located differently and an alchemical transformation&#13;
of butane to pentane where the dimension of the state space is changed.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-46718</identifier>
    <identifier type="doi">10.1080/00268976.2014.944597</identifier>
    <enrichment key="SourceTitle">appeared in: Mol. Phys. 2014 (epub ahead of print)</enrichment>
    <author>Christof Schütte</author>
    <submitter>Adam Nielsen</submitter>
    <author>Adam Nielsen</author>
    <author>Marcus Weber</author>
    <series>
      <title>ZIB-Report</title>
      <number>14-05</number>
    </series>
    <subject>
      <language>deu</language>
      <type>uncontrolled</type>
      <value>Girsanov Theorem</value>
    </subject>
    <subject>
      <language>deu</language>
      <type>uncontrolled</type>
      <value>Stochastic Differential Equation</value>
    </subject>
    <subject>
      <language>deu</language>
      <type>uncontrolled</type>
      <value>Importance Sampling</value>
    </subject>
    <collection role="msc" number="60J70">Applications of Brownian motions and diffusion theory (population genetics, absorption problems, etc.) [See also 92Dxx]</collection>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="TransRisk">TransRisk</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/4671/article_zib.pdf</file>
  </doc>
  <doc>
    <id>5794</id>
    <completedYear/>
    <publishedYear>2016</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>1319</pageFirst>
    <pageLast>1340</pageLast>
    <pageNumber/>
    <edition/>
    <issue>4</issue>
    <volume>14</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Finding dominant structures of nonreversible Markov processes</title>
    <parentTitle language="eng">Multiscale Modeling and Simulation</parentTitle>
    <identifier type="doi">10.1137/15M1032272</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="PreprintUrn">urn:nbn:de:0297-zib-55739</enrichment>
    <author>Natasa Djurdjevac Conrad</author>
    <submitter>Regine Kossick</submitter>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="BMS-Nielsen">BMS-Nielsen</collection>
    <collection role="projects" number="EyeTracking">EyeTracking</collection>
    <collection role="projects" number="MODAL-MedLab">MODAL-MedLab</collection>
    <collection role="projects" number="NonequiMSM">NonequiMSM</collection>
    <collection role="projects" number="TransRisk">TransRisk</collection>
    <collection role="persons" number="natasa.conrad">Conrad, Natasa</collection>
    <collection role="projects" number="MODAL-Gesamt">MODAL-Gesamt</collection>
  </doc>
  <doc>
    <id>8274</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>607</issue>
    <volume>13</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2023-01-12</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design</title>
    <abstract language="eng">We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.</abstract>
    <parentTitle language="eng">Scientific Reports</parentTitle>
    <identifier type="doi">10.1038/s41598-023-27699-w</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="AcceptedDate">2023-01-06</enrichment>
    <author>Arne Thies</author>
    <submitter>Erlinda Körnig</submitter>
    <author>Vikram Sunkara</author>
    <author>Sourav Ray</author>
    <author>Hanna Wulkow</author>
    <author>M. Özgür Celik</author>
    <author>Fatih Yergöz</author>
    <author>Christof Schütte</author>
    <author>Christoph Stein</author>
    <author>Marcus Weber</author>
    <author>Stefanie Winkelmann</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="institutes" number="compmol">Computational Molecular Design</collection>
    <collection role="institutes" number="compsys">Computational Systems Biology</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-C3">SFB1114-C3</collection>
    <collection role="persons" number="winkelmann">Winkelmann, Stefanie</collection>
    <collection role="persons" number="sunkara">Sunkara, Vikram</collection>
    <collection role="projects" number="MathPlusAA1-1">MathPlusAA1-1</collection>
    <collection role="institutes" number="MfLMS">Mathematics for Life and Materials Science</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <collection role="projects" number="MathPlusAA1-5">MathPlusAA1-5</collection>
    <collection role="projects" number="MathPlusAA1-15">MathPlusAA1-15</collection>
  </doc>
  <doc>
    <id>8279</id>
    <completedYear/>
    <publishedYear/>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>reportzib</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>2021-07-07</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design</title>
    <abstract language="eng">Initiated by mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands in normal versus diseased (inflamed) environments, we previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. Uniquely, this design recognised that GPCRs function differently under pathological versus healthy conditions. &#13;
We now present a novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels associated with parameters of inflamed tissue (pH, radicals). By means of molecular dynamics simulations, we also assessed qualitative changes of the reaction rates due to additional disulfide bridges inside the GPCR binding pocket and used these rates for stochastic simulations of the corresponding reaction jump process. &#13;
The modelling results were validated with in vitro experiments measuring calcium currents and G-protein activation. &#13;
We found markedly reduced G-protein dissociation and calcium channel inhibition induced by NFEPP at normal pH, and enhanced constitutive G-protein activation but lower probability of ligand binding with increasing radical concentrations. &#13;
These results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.</abstract>
    <identifier type="issn">1438-0064</identifier>
    <identifier type="urn">urn:nbn:de:0297-zib-82797</identifier>
    <enrichment key="opus.source">publish</enrichment>
    <author>Sourav Ray</author>
    <submitter>Stefanie Winkelmann</submitter>
    <author>Arne Thies</author>
    <author>Vikram Sunkara</author>
    <author>Hanna Wulkow</author>
    <author>Özgür Celik</author>
    <author>Fatih Yergöz</author>
    <author>Christof Schütte</author>
    <author>Christoph Stein</author>
    <author>Marcus Weber</author>
    <author>Stefanie Winkelmann</author>
    <series>
      <title>ZIB-Report</title>
      <number>21-19</number>
    </series>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="persons" number="winkelmann">Winkelmann, Stefanie</collection>
    <collection role="persons" number="sunkara">Sunkara, Vikram</collection>
    <collection role="projects" number="MathPlusAA1-1">MathPlusAA1-1</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <file>https://opus4.kobv.de/opus4-zib/files/8279/ZIB-Report.pdf</file>
  </doc>
  <doc>
    <id>10070</id>
    <completedYear/>
    <publishedYear>2025</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>13</issue>
    <volume>26</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2025-06-27</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Investigating Endogenous Opioids Unravels the Mechanisms Behind Opioid-Induced Constipation, a Mathematical Modeling Approach</title>
    <abstract language="eng">Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC.</abstract>
    <parentTitle language="eng">International Journal of Molecular Sciences</parentTitle>
    <identifier type="doi">10.3390/ijms26136207</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="AcceptedDate">2025-06-24</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <author>Celvic Coomber</author>
    <submitter>Stefanie Winkelmann</submitter>
    <author>Surahit Chewle</author>
    <author>Christopher Secker</author>
    <author>Konstantin Fackeldey</author>
    <author>Marcus Weber</author>
    <author>Stefanie Winkelmann</author>
    <author>Christof Schütte</author>
    <author>Vikram Sunkara</author>
    <collection role="persons" number="fackeldey">Fackeldey, Konstantin</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <collection role="projects" number="SFB1114-C3">SFB1114-C3</collection>
    <collection role="persons" number="winkelmann">Winkelmann, Stefanie</collection>
    <collection role="persons" number="sunkara">Sunkara, Vikram</collection>
    <collection role="institutes" number="scp">Supercomputing</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <collection role="institutes" number="VDcC">Visual and Data-centric Computing</collection>
    <collection role="persons" number="coomber">Coomber, Celvic</collection>
    <collection role="persons" number="chewle">Chewle, Surahit</collection>
    <collection role="projects" number="MathPlusAA1-15">MathPlusAA1-15</collection>
    <collection role="persons" number="secker">Secker, Christopher</collection>
    <collection role="projects" number="CCMAI">CCMAI</collection>
    <collection role="projects" number="MathPlusAA1-19">MathPlusAA1-19</collection>
  </doc>
  <doc>
    <id>9027</id>
    <completedYear/>
    <publishedYear>2023</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume>15</volume>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">Novel multi-objective affinity approach allows to identify pH-specific μ-opioid receptor agonists</title>
    <abstract language="eng">Opioids are essential pharmaceuticals due to their analgesic properties, however, lethal side effects, addiction, and opioid tolerance are extremely challenging. The development of novel molecules targeting the μ-opioid receptor (MOR) in inflamed, but not in healthy tissue, could significantly reduce these unwanted effects. Finding such novel molecules can be achieved by maximizing the binding affinity to the MOR at acidic pH while minimizing it at neutral pH, thus combining two conflicting objectives. Here, this multi-objective optimal affinity approach is presented, together with a virtual drug discovery pipeline for its practical implementation. When applied to finding pH-specific drug candidates, it combines protonation state-dependent structure and ligand preparation with high-throughput virtual screening. We employ this pipeline to characterize a set of MOR agonists identifying a morphine-like opioid derivative with higher predicted binding affinities to the MOR at low pH compared to neutral pH. Our results also confirm existing experimental evidence that NFEPP, a previously described fentanyl derivative with reduced side effects, and recently reported β-fluorofentanyls and -morphines show an increased specificity for the MOR at acidic pH when compared to fentanyl and morphine. We further applied our approach to screen a &gt;50K ligand library identifying novel molecules with pH-specific predicted binding affinities to the MOR. The presented differential docking pipeline can be applied to perform multi-objective affinity optimization to identify safer and more specific drug candidates at large scale.</abstract>
    <parentTitle language="eng">Journal of Cheminformatics</parentTitle>
    <identifier type="doi">10.1186/s13321-023-00746-4</identifier>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="AcceptedDate">2023-08-23</enrichment>
    <author>Christopher Secker</author>
    <submitter>Ekaterina Engel</submitter>
    <author>Konstantin Fackeldey</author>
    <author>Marcus Weber</author>
    <author>Sourav Ray</author>
    <author>Christoph Gorgulla</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="fackeldey">Fackeldey, Konstantin</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
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    <collection role="projects" number="MODAL-Gesamt">MODAL-Gesamt</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <collection role="institutes" number="Mathematical Algorithmic Intelligence">Mathematical Algorithmic Intelligence</collection>
    <collection role="institutes" number="PaDC">Parallel and Distributed Computing</collection>
    <collection role="persons" number="gorgulla">Gorgulla, Christoph</collection>
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    <collection role="persons" number="secker">Secker, Christopher</collection>
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  <doc>
    <id>8013</id>
    <completedYear/>
    <publishedYear>2021</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>4</issue>
    <volume>4</volume>
    <type>article</type>
    <publisherName>Wiley-VCH</publisherName>
    <publisherPlace/>
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    <completedDate>2021-03-09</completedDate>
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    <title language="eng">The Augmented Jump Chain</title>
    <abstract language="eng">Modern methods of simulating molecular systems are based on the mathematical theory of Markov operators with a focus on autonomous equilibrated systems. However, non-autonomous physical systems or non-autonomous simulation processes are becoming more and more important. A representation of non-autonomous Markov jump processes is presented as autonomous Markov chains on space-time. Augmenting the spatial information of the embedded Markov chain by the temporal information of the associated jump times, the so-called augmented jump chain is derived. The augmented jump chain inherits the sparseness of the infinitesimal generator of the original process and therefore provides a useful tool for studying time-dependent dynamics even in high dimensions. Furthermore, possible generalizations and applications to the computation of committor functions and coherent sets in the non-autonomous setting are discussed. After deriving the theoretical foundations, the concepts with a proof-of-concept Galerkin discretization of the transfer operator of the augmented jump chain applied to simple examples are illustrated.</abstract>
    <parentTitle language="eng">Advanced Theory and Simulations</parentTitle>
    <identifier type="arxiv">2008.04624</identifier>
    <identifier type="doi">10.1002/adts.202000274</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="AcceptedDate">2021-01-05</enrichment>
    <author>Alexander Sikorski</author>
    <submitter>Alexander Sikorski</submitter>
    <author>Marcus Weber</author>
    <author>Christof Schütte</author>
    <collection role="institutes" number="num">Numerical Mathematics</collection>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB1114-A5">SFB1114-A5</collection>
    <collection role="persons" number="sikorski">Sikorski, Alexander</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
  </doc>
  <doc>
    <id>9452</id>
    <completedYear/>
    <publishedYear>2025</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>e2356748</pageFirst>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue>7-8: Giovanni Ciccotti: A Renaissance Physicist</issue>
    <volume>123</volume>
    <type>article</type>
    <publisherName>Taylor &amp; Francis</publisherName>
    <publisherPlace/>
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    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>2024-05-25</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">The Kramers turnover in terms of a macro-state projection on phase space</title>
    <abstract language="eng">We have investigated how Langevin dynamics is affected by the friction&#13;
coefficient using the novel algorithm ISOKANN, which combines the transfer&#13;
operator approach with modern machine learning techniques. ISOKANN describes&#13;
the dynamics in terms of an invariant subspace projection of the Koopman&#13;
operator defined in the entire state space, avoiding approximations due to&#13;
dimensionality reduction and discretization. Our results are consistent with&#13;
the Kramers turnover and show that in the low and moderate friction regimes,&#13;
metastable macro-states and transition rates are defined in phase space, not&#13;
only in position space.</abstract>
    <parentTitle language="eng">Molecular Physics</parentTitle>
    <identifier type="doi">10.1080/00268976.2024.2356748</identifier>
    <enrichment key="PeerReviewed">yes</enrichment>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="AcceptedDate">13 May 2024</enrichment>
    <author>Luca Donati</author>
    <submitter>Luca Donati</submitter>
    <author>Christof Schütte</author>
    <author>Marcus Weber</author>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="projects" number="SFB-1114-B3">SFB-1114-B3</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <collection role="projects" number="MathPlusAA1-15">MathPlusAA1-15</collection>
    <collection role="persons" number="donati">Donati, Luca</collection>
  </doc>
  <doc>
    <id>10314</id>
    <completedYear/>
    <publishedYear>2026</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume/>
    <type>article</type>
    <publisherName/>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">On-the-Fly Lifting of Coarse Reaction-Coordinate Paths to Full-Dimensional Transition Path Ensembles</title>
    <abstract language="eng">Effective dynamics on a low-dimensional collective-variable (CV) or latent space can be simulated far more cheaply than the underlying high-dimensional stochastic system, but exploiting such coarse predictions requires lifting: turning a coarse CV trajectory into dynamically consistent full-dimensional states and path ensembles, without relying on global sampling of invariant or conditional fiber measures. We present a local, on-the-fly lifting strategy based on guided full-system trajectories. First an effective model in CV space is used to obtain a coarse reference trajectory. Then, an ensemble of full-dimensional trajectories is generated from a guided version of the original dynamics, where the guidance steers the trajectory to track the CV reference path. Because guidance biases the path distribution, we correct it via pathwise Girsanov reweighting, yielding a correct-by-construction importance-sampling approximation of the conditional law of the uncontrolled dynamics. We further connect the approach to stochastic optimal control, clarifying how coarse models can inform variance-reducing guidance for rare-event quantities. Numerical experiments demonstrate that inexpensive coarse transition paths can be converted into realistic full-system transition pathways (including barrier crossings and detours) and can accelerate estimation of transition pathways and statistics while providing minimal bias through weighted ensembles.</abstract>
    <identifier type="doi">10.48550/arXiv.2603.23266</identifier>
    <identifier type="arxiv">2603.23266</identifier>
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    <author>Christof Schütte</author>
    <submitter>Alexander Sikorski</submitter>
    <author>Alexander Sikorski</author>
    <author>Jakob Kresse</author>
    <author>Marcus Weber</author>
    <collection role="persons" number="schuette">Schütte, Christof</collection>
    <collection role="persons" number="weber">Weber, Marcus</collection>
    <collection role="persons" number="sikorski">Sikorski, Alexander</collection>
    <collection role="projects" number="SFB-1114-B3">SFB-1114-B3</collection>
    <collection role="institutes" number="MSoCP">Modeling and Simulation of Complex Processes</collection>
    <collection role="persons" number="kresse">Kresse, Jakob</collection>
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