Marcus Kubitzki

Today's standard molecular dynamics (MD) simulations of moderately sized biomolecular systems at full atomic resolution are typically limited to the sub-microsecond timescale and therefore suffer from limited conformational sampling. Efficient ensemble-preserving algorithms like replica exchange (REX) may alleviate this problem somewhat but are still computationally prohibitive due to the large number of degrees of freedom involved.

Aiming at increased sampling efficiency we developed the novel TEE-REX simulation method combining the ideas of essential dynamics and REX. Unlike normal REX, in each replica only a selection of essential collective modes of a subsystem of interest are coupled to a higher temperature with the remainder of the system staying at a reference temperature T_0. This selective excitation along with the replica framework permits efficient ensemble-preserving sampling of the relevant degrees of freedom and allows for much larger temperature spacings between replicas, thereby considerably enhancing sampling efficiency. In this project, statistical properties and sampling performance of the method are discussed on several test systems and compared to sub-microsecond MD simulations.

Due to the specific excitation along collective coordinates, large conformational transitions can be studied with the TEE-REX algorithm. As a first test case we investigated in atomic detail the spontaneous conformational transition of E. coli adenylate kinase (ADK), a ubiquitous enzyme playing a key role in energy maintenance within the cell by controlling cellular ATP levels. Crystallographic structures of a substrate-free "open" and a bound "closed" conformation are known, implying a major conformational transition. Recent studies on coarse-grained models suggest a certain pathway, but up to now a detailed atomistic understanding of possible transition pathways is lacking. Using TEE-REX a transition pathway could be characterized, yielding detailed insights into the atomistic mechanisms of the transition.

Often, conformational transitions are allosteric in nature. With TEE-REX, we have a powerful and flexible tool at hand to study allosteric transitions. In this project, we apply TEE-REX to several proteins, to obtain and understand atomic details of the respective allosteric mechanism.