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While seemingly straightforward in principle, the reliable estimation of rate constants is seldom easy in practice. Numerous issues, such as the complication of poor reaction coordinates, cause obvious approaches to yield unreliable estimates. When a reliable order parameter is available, the reactive flux theory of Chandler allows the rate constant to be extracted from the plateau region of an appropriate reactive flux correlation function. However, when applied to real data from single- molecule experiments or molecular dynamics simulations, the reactive flux correlation function requires the numerical differentiation of a noisy empirical correlation function, which can result in an unacceptably poor estimate of the rate and pathological dependence on the sampling interval. We present a modified version of this theory which does not require numerical derivatives, allowing rate constants to be robustly estimated from the time-correlation function directly. We illustrate the approach using single-molecule passive force spectroscopy measurements of an RNA hairpin.
Single-molecule force spectroscopy has proven to be a powerful tool for studying the kinetic be- havior of biomolecules. Through application of an external force, conformational states with small or transient populations can be stabilized, allowing them to be characterized and the statistics of in- dividual trajectories studied to provide insight into biomolecular folding and function. Because the observed quantity (force or extension) is not necessarily an ideal reaction coordinate, individual ob- servations cannot be uniquely associated with kinetically distinct conformations. While maximum- likelihood schemes such as hidden Markov models have solved this problem for other classes of single-molecule experiments by using temporal information to aid in the inference of a sequence of distinct conformational states, these methods do not give a clear picture of how precisely the model parameters are determined by the data due to instrument noise and finite-sample statistics, both sig- nificant problems in force spectroscopy. We solve this problem through a Bayesian extension that allows the experimental uncertainties to be directly quantified, and build in detailed balance to fur- ther reduce uncertainty through physical constraints. We illustrate the utility of this approach in characterizing the three-state kinetic behavior of an RNA hairpin in a stationary optical trap.
In multicriteria optimization, a compromise solution is a feasible solution whose
cost vector minimizes the distance to the ideal point w.r.t. a given norm. The coor-
dinates of the ideal point are given by the optimal values for the single optimization
problem for each criterion.
We show that the concept of compromise solutions ts nicely into the existing
notion of Pareto optimality: For a huge class of norms, every compromise solution
is Pareto optimal, and under certain conditions on the norm all Pareto optimal so-
lution are also a compromise solution, for an appropriate weighting of the criteria.
Furthermore, under similar conditions on the norm, the existence of an FPTAS for
compromise solutions guarantees the approximability of the Pareto set.
These general results are completed by applications to classical combinatorial
optimization problems. In particular, we study approximation algorithms for the
multicriteria shortest path problem and the multicriteria minimum spanning tree
problem. On the one hand, we derive approximation schemes for both problems, on
the other hand we show that for the latter problem simple approaches like local search
and greedy techniques do not guarantee good approximation factors.
We solve Skorokhod's embedding problem for Brownian motion with linear drift $(W_t+ \kappa t)_{t\geq 0}$ by means of techniques of stochastic control theory. The search for a stopping time
$T$ such that the law of $W_T + \kappa T$ coincides with a prescribed law $\mu$ possessing the first
moment is based on solutions of backward stochastic differential equations of quadratic
type. This new approach generalizes an approach by Bass [Bas] of the classical version of
Skorokhod's embedding problem using martingale representation techniques.
We consider a dynamical system described by the differential equation $\dot{Y}_t = -U^'(Y_t)$
with a unique stable point at the origin. We perturb the system by L\'evy noise of
intensity $\varepsilon$, to obtain the stochastic differential equation $dX^\varepsilon_t = -U^'(X^\varepsilon_{t-})dt + \varepsilon dL_t}.
The process $L$ is a symmetric L\'evy process whose jump measure $\nu$ has exponentially
light tails, $\nu([u, \infty))\sim exp(-u^\alpha), \alpha > 0, u \to\infty$. We study the first exit problem for
the trajectories of the solutions of the stochastic differential equation from the interval
$[-1, 1]$. In the small noise limit $\varepsilon\to 0$ we determine the law and the mean value of the
first exit time, to discover an intriguing phase transition at the critical index $\alpha = 1$.
In a strong constant electric field, a dielectric particle immersed in a weakly conducting fluid exhibits spontaneous rotations. This phenomenon is known under the name of the Quincke effect. In the original setup the particle was suspended on a silk thread and performed torsional oscillations of remarkably high amplitude. We derive the governing equations for this experiment, and ascertain
that onset of oscillations from the quiescent state corresponds to the supercritical Hopf bifurcation.
For the case of a soft thread, we characterize the regime of large-scale torsional relaxation oscillations:
explicit estimates are derived for their period and amplitude, effects of bifurcation delay are described. In a stronger electric field, these relaxation oscillations yield to small-scale erratic rotations of the pendulum.
Markov state models have become very popular for the description of conformation dynamics of molecules over
long timescales. The construction of such models requires a partitioning of the configuration space such that the discretization
can serve as an approximation of metastable conformations. Since the computational complexity for the construction of a
Markov state model increases quadratically with the number of sets, it is desirable to obtain as few sets as necessary. In this
paper we propose an algorithm for the adaptive refinement of an initial coarse partitioning. A spectral clustering method is
applied to the final partitioning to detect the metastable conformations. We apply this method to the conformation analysis of
a model tri-peptide molecule, where metastable beta- and gamma-turn conformations can be identified.
Supercomputers can simulate complex molecular systems. However, there is a very large gap between the fastest oscillations of covalent bonds of a molecule and the time-scale of the dominant processes. In order to extract the dominant time-scales and to identify the dominant processes, a clustering of information is needed. This thesis shows that only the subspace-based Robust Perron Cluster Analysis (PCCA+) can solve this problem correctly by the construction of a Markov State Model. PCCA+ allows for time-extrapolation in molecular kinetics. This thesis shows the difference between molecular dynamics and molecular kinetics. Only in the molecular kinetics framework a definition of transition rates is possible. In this context, the existence of an infinitesimal generator of the dynamical processes is discussed. If the existence is assumed, the Theorem of Gauß can be applied in order to compute transition rates efficiently. Molecular dynamics, however, is not able to provide a suitable statistical basis for the determination of the transition pattern.