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. Assessing these uncertainties is essential for testing the reliability of a given observation and also, if possible, to plan further simulations or measurements in such a way that the most serious uncertainties will be reduced with minimal effort. Here, a rigorous statistical method is proposed to approximate the complete statistical distribution of functions of the transition matrix provided that one can identify discrete states such that the transition process between them may be modeled with a memoryless jump process, i.e., Markov dynamics. The method is based on sampling the statistical distribution of Markov transition matrices that is induced by the observed transition events. It allows the constraint of reversibility to be included, which is physically meaningful in many applications. The method is illustrated on molecular dynamics simulations of a hexapeptide that are modeled by a Markov transition process between the metastable states. For this model the distributions and uncertainties of the stationary probabilities of metastable states, the transition matrix elements, the committor probabilities, and the transition matrix eigenvalues are estimated. It is found that the detailed balance constraint can significantly alter the distribution of some observables

On the Approximation Quality of Markov State Models

We consider a continuous-time Markov process on a large continuous or discrete state space. The process is assumed to have strong enough ergodicity properties and to exhibit a number of metastable sets. Markov state models (MSMs) are designed to represent the effective dynamics of such a process by a Markov chain that jumps between the metastable sets with the transition rates of the original process. MSMs have been used for a number of applications, including molecular dynamics, for more than a decade. Their approximation quality, however, has not yet been fully understood. In particular, it would be desirable to have a sharp error bound for the difference in propagation of probability densities between the MSM and the original process on long timescales. Here, we provide such a bound for a rather general class of Markov processes ranging from diffusions in energy landscapes to Markov jump processes on large discrete spaces. Furthermore, we discuss how this result provides formal support or shows the limitations of algorithmic strategies that have been found to be useful for the construction of MSMs. Our findings are illustrated by numerical experiments

Data-based Parameter Estimation of Generalized Multidimensional Langevin Processes

The generalized Langevin equation is useful for modeling a wide range of physical processes. Unfortunately its parameters, especially the memory function, are difficult to determine for nontrivial processes. We establish relations between a time-discrete generalized Langevin model and discrete multivariate autoregressive (AR) or autoregressive moving average models (ARMA). This allows a wide range of discrete linear methods known from time series analysis to be applied. In particular, the determination of the memory function via the order of the respective AR or ARMA model is addressed. The method is illustrated on a one-dimensional test system and subsequently applied to the molecular dynamics time series of a biomolecule that exhibits an interesting relationship between the solvent method used, the respective molecular conformation, and the depth of the memory

Development of Acid-Sensitive Platinum(II) Complexes With Protein-Binding Properties

Four new protein-binding platinum(II) complexes, 10, 11, 21, 22, in which the dichloroplatinum moiety is coordinated either to a carbon-substituted or a nitrogen-substituted ethylene diamino ligand, were prepared in ten-step syntheses. According to pH-dependent stability studies with strictly related compounds, 11 and 22 exhibit acid-sensitive properties

Hierarchical Analysis of Conformational Dynamics in Biomolecules: Transition Networks of Metastable States

Molecular dynamics simulation generates large quantities of data that must be interpreted using physically meaningful analysis. A common approach is to describe the system dynamics in terms of transitions between coarse partitions of conformational space. In contrast to previous work that partitions the space according to geometric proximity, the authors examine here clustering based on kinetics, merging configurational microstates together so as to identify long-lived, i.e., dynamically metastable, states. As test systems microsecond molecular dynamics simulations of the polyalanines Ala8 and Ala12 are analyzed. Both systems clearly exhibit metastability, with some kinetically distinct metastable states being geometrically very similar. Using the backbone torsion rotamer pattern to define the microstates, a definition is obtained of metastable states whose lifetimes considerably exceed the memory associated with interstate dynamics, thus allowing the kinetics to be described by a Markov model. This model is shown to be valid by comparison of its predictions with the kinetics obtained directly from the molecular dynamics simulations. In contrast, clustering based on the hydrogen-bonding pattern fails to identify long-lived metastable states or a reliable Markov model. Finally, an approach is proposed to generate a hierarchical model of networks, each having a different number of metastable states. The model hierarchy yields a qualitative understanding of the multiple time and length scales in the dynamics of biomolecule