HIV-1 polymerase inhibition by nucleoside analogs: cellular- and kinetic parameters of efficacy, susceptibility and resistance selection.

Nucleoside analogs (NAs) are used to treat numerous viral infections and cancer. They compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA and inhibit replication by preventing subsequent primer extension. To date, an integrated mathematical model that could allow the analysis of their mechanism of action, of the various resistance mechanisms, and their effect on viral fitness is still lacking.

Mechanisms of protein-ligand association and its modulation by protein mutations.

Protein-ligand interactions are essential for nearly all biological processes, and yet the biophysical mechanism that enables potential binding partners to associate before specific binding occurs remains poorly understood. Fundamental questions include which factors influence the formation of protein-ligand encounter complexes, and whether designated association pathways exist. To address these questions, we developed a computational approach to systematically analyze the complete ensemble of association pathways.

Observation uncertainty in reversible Markov chains.

In many applications one is interested in finding a simplified model which captures the essential dynamical behavior of a real life process. If the essential dynamics can be assumed to be (approximately) memoryless then a reasonable choice for a model is a Markov model whose parameters are estimated by means of Bayesian inference from an observed time series. We propose an efficient Monte Carlo Markov chain framework to assess the uncertainty of the Markov model and related observables.

Estimating the sampling error: distribution of transition matrices and functions of transition matrices for given trajectory data.

The problem of estimating a Markov transition matrix to statistically describe the dynamics underlying an observed process is frequently found in the physical and economical sciences. However, little attention has been paid to the fact that such an estimation is associated with statistical uncertainty, which depends on the number of observed transitions between metastable states. In turn, this induces uncertainties in any property computed from the transition matrix, such as stationary probabilities, committor probabilities, or eigenvalues.

Generator estimation of Markov jump processes based on incomplete observations nonequidistant in time.

Markov jump processes can be used to model the effective dynamics of observables in applications ranging from molecular dynamics to finance. In this paper we present a different method which allows the inverse modeling of Markov jump processes based on incomplete observations in time: We consider the case of a given time series of the discretely observed jump process. We show how to compute efficiently the maximum likelihood estimator of its infinitesimal generator and demonstrate in detail that the method allows us to handle observations nonequidistant in time.

Illustration of transition path theory on a collection of simple examples.

Transition path theory (TPT) has been recently introduced as a theoretical framework to describe the reaction pathways of rare events between long lived states in complex systems. TPT gives detailed statistical information about the reactive trajectories involved in these rare events, which are beyond the realm of transition state theory or transition path sampling. In this paper the TPT approach is outlined, its distinction from other approaches is discussed, and, most importantly, the main insights and objects provided by TPT are illustrated in detail via a series of low dimensional test problems.