Abstract

Molecular dynamics simulation can in principle provide useful predictions of processes involving protein conformational changes on an atomistic level that are complementary to experiment. However, in practice, all atom molecular dynamics is often limited to small systems due to the long simulation times required for such processes to take place. It is possible to bridge these long time scales by realizing that many processes such as (un)folding and other conformational changes in proteins in fact are rare events caused by (high) free energy barriers between stable states. To overcome such barriers, many techniques have been developed, e.g. replica exchange, metadynamics, and transition path sampling. While proper sampling is important, only proper analysis of the simulation results can yield insight. Proteins can adopt many configurations, and it is not always easy to identify stable or metastable states and transitions between them. The development of methods that describe protein dynamics in terms of equilibrium kinetic networks or Markov state models have made such analysis possible. In addition, we have recently developed methods that allow the prediction of relevant reaction coordinates.

In this presentation I will discuss the need for such rare event simulation methods and will exemplify them on applications such as conformational changes in (signaling) proteins, and amyloid fibril growth. In each case we can gain insight in mechanisms of processes that are normally beyond the limit of straightforward molecular dynamics.