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    <title>OPUS 4 Latest Documents RSS Feed</title>
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    <link>http://opus4.kobv.de/opus4-ubbayreuth/index/index/</link>
    <pubDate>Tue, 12 Jun 2012 11:05:09 +0100</pubDate>
    <lastBuildDate>Tue, 12 Jun 2012 11:05:09 +0100</lastBuildDate>
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      <title>Monte Carlo Simulation Methods for Studying the Thermodynamics of Ligand Binding &amp; Transfer Processes in Biomolecules</title>
      <link>http://opus4.kobv.de/opus4-ubbayreuth/frontdoor/index/index/docId/1022</link>
      <description>The binding and transfer of ligands is of central&#13;
importance for the function of many biomolecular&#13;
systems. The main topic of this thesis is the&#13;
development and application of Monte Carlo (MC)&#13;
simulation methods for studying complex ligand&#13;
binding equilibria which can also involve&#13;
conformational changes. The simulated systems&#13;
were described by microstates within a continuum&#13;
electrostatics/molecular mechanics (CE/MM) model&#13;
of the receptor-ligand system. The CE/MM modeling&#13;
methodology was improved. The improvements led to&#13;
more detailed molecular models that enable a more&#13;
realistic reproduction of system properties and&#13;
environmental conditions. The developed simulation&#13;
methods were applied to biomolecular systems whose&#13;
function involves aspects that are important for&#13;
the understanding of bioenergetic energy&#13;
transduction. The results of this thesis are&#13;
presented in five articles that are published in&#13;
peer reviewed scientific journals.&#13;
&#13;
Manuscript A presents the Monte Carlo simulation&#13;
software GMCT which was largely developed in this&#13;
thesis. The software offers a variety of different&#13;
simulation methods that allow the user to harness&#13;
the full potential of CE/MM models in the simulation&#13;
of complex receptor systems.&#13;
&#13;
Manuscript B presents a novel theoretical framework&#13;
for free energy calculations with the free energy&#13;
perturbation method. The novel framework is more&#13;
broadly applicable and can lead to more efficient&#13;
simulations than previous formulations. The&#13;
derivation of the formalism also led to interesting&#13;
insights into general statistical mechanics. The&#13;
formalism was implemented in GMCT and could already&#13;
be used fruitfully for the free energy calculations &#13;
presented in Manuscripts C and D.&#13;
&#13;
Manuscript C demonstrates the application of free&#13;
energy measures of cooperativity to study the&#13;
coupling of protonation, reduction and conformational&#13;
change in azurin from Pseudomonas aeruginosa (PaAz).&#13;
Such a coupling is prototypic for bioenergetic systems&#13;
because it forms the thermodynamic basis of their&#13;
energy transducing function. PaAz is an experimentally&#13;
well characterized, small electron transport protein.&#13;
For this reason, PaAz was used here as model system&#13;
to demonstrate the usefulness of cooperativity free&#13;
energies in detecting and quantifying thermodynamic&#13;
coupling between events in complex biomolecular&#13;
systems. The results of this study led to new insight&#13;
that could help to determine the still enigmatic&#13;
physiological role of PaAz.&#13;
&#13;
In Manuscript D, free energy calculations were&#13;
applied to study the thermodynamics of transport&#13;
through the ammonium transporter Amt-1 from&#13;
Archaeoglobus fulgidus (AfAmt-1). Ammonium is the most&#13;
directly utilizable nitrogen source for plants and&#13;
microorganisms. AfAmt-1 and its homologues facilitate&#13;
the transport of ammonia/ammonium across biological&#13;
membranes in living beings from all domains of life.&#13;
It is intensely debated how these proteins perform&#13;
their function and whether ammonia or its protonated&#13;
form ammonium is actually transported. The study&#13;
extended upon previous theoretical studies by&#13;
including the effects of substrate concentration,&#13;
electrochemical transmembrane gradients,&#13;
proton-coupled binding equilibria and competitive&#13;
binding of different ligand species. It was found&#13;
that the transported species is most likely the&#13;
ammonium ion. An ammonia/proton symport mechanism&#13;
that involves a pair of coplanar histidine residues&#13;
at the center of the transmembrane pore as transient&#13;
proton acceptor is made plausible by the high&#13;
genetic conservation of these residues.&#13;
&#13;
Manuscript E presents a first application of the&#13;
microstate description within a CE/MM model to the&#13;
simulation of the non-equilibrium dynamics of a&#13;
molecular system. We simulated the re-reduction&#13;
kinetics of the primary electron donor in the&#13;
photocycle of the bacterial photosynthetic reaction&#13;
center from Blastochloris viridis. The simulation&#13;
results are in very good agreement with&#13;
experimentally measured data.</description>
      <author>R. Thomas Ullmann</author>
      <category>doctoralthesis</category>
      <guid>http://opus4.kobv.de/opus4-ubbayreuth/frontdoor/index/index/docId/1022</guid>
      <pubDate>Thu, 06 Dec 2012 11:05:09 +0100</pubDate>
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