1. State of the art – Protein dynamics at the interface of cutting-edge simulations and experiments
In their quest to understand the mechanisms of life, biologists have gone from observing, e.g., the development and motions of entire organisms, cells and cellular organelles, all the way to the atomic level at which biomacromolecules perform the groundwork for macroscopic life. The more than 140.000 known 3D structures of proteins resolved at the Ångstrom level have provided tremendous insight into protein function. However, the vast details contained in these structures is somewhat deceptive, as they represent a single static snapshot obtained, in most cases, by trapping a protein inside a frozen crystal. Such a static view is hardly representative of the dynamic nature of life. Processes such as enzymatic turnover, protein transport and folding via biomolecular machinery (chaperoning), or the translocation of small molecules across biological membranes fundamentally involve the sampling of multiple conformations of the proteins involved, i.e., dynamics. Moreover, the realization that many proteins are functional despite lacking any defined 3D structure has severely challenged our view of the structure-function relationship. Understanding the inner workings and functioning of any machine requires to know not only its “parts and components” and their structural arrangement, but also “seeing” how the parts move and interact with each other. This picture is very valid also for the “nanomachines” that are proteins.
The study of complex biomolecular dynamics is a considerable challenge, as it requires not only to determine a set of atomic coordinates in 3D space, but also how they evolve in a fourth dimension, time. No single experimental technique is able to achieve this task by itself. Remarkable developments over the last decade, enabled by steady progress and ground-breaking new technologies both in computational algorithms and experimental approaches have, however, provided much insight into the dynamics of proteins, often by merging different experimental approaches and computational methods. Increasingly, the spatial and temporal domains accessible to state-of-the-art computational models and experiments are commensurate, providing opportunities for previously unprecedented critical comparisons of the predictions of computational models as well as the molecular-level interpretation of experimental data. Much progress has been achieved by combining data from different experimental techniques, and often such integration is achieved through molecular simulations. Arguably, connecting experimental with computational data has turned out to be game-changing in order to understand the function of increasingly complex biomolecular systems at ever-growing details.
Important challenges remain to be overcome both for experimental and computational approaches. For example, a particularly important and active research field in computational biophysics aims at simulating molecular dynamics over sufficient time scales (micro- to milliseconds) to observe the biologically relevant conformational changes, which coincide with many biomolecular processes (e.g. enzymatic turnover). Computational investigation of millisecond events in large biological objects is computationally very expensive. Enhanced sampling and accelerated simulation methods are often limited by our ability to identify the relevant degrees of freedom at play and sample them with utmost efficiency. Pushing the limits of computer simulations with new hardware and algorithms to longer time scales and larger system sizes is therefore a topic of central importance. Another active research area is related to understanding the solvation of biomacromolecules through computational and experimental approaches. The Les Houches – TSRC Workshop on Protein Dynamics brings together the latest developments in various computational and experimental fields, aiming to stimulate mutual benefits from this cross-disciplinary contact.