9.3 In Silico Coarse-Grained Approaches to Structural Dynamics and Function of Proteins and their Assemblies

Abstract

Comparison of computational and experimental data in recent years highlights the significance of the intrinsic dynamics of proteins in facilitating, or enabling, biological functions. Intrinsic dynamics refer to the collective motions encoded in the native structure, predominantly defined by the network of inter-residue interactions. Elastic network models (ENMs) coupled with normal mode analyses have proven in recent years to serve as useful computational tools for elucidating such intrinsic propensities. In particular, the soft modes predicted by ENMs disclose cooperative mechanisms of reconfiguration, which relate to structural changes undergone during allosteric responses or molecular machinery. We present here in silico approaches based on ENMs of various levels of granularity, along with several examples of their use in unraveling biomolecular mechanisms of function, including their application to supramolecular systems dynamics such as the bacterial chaperonin GroEL and the ribosome. We also highlight the significance of complementing ENM-based studies by sequence-based correlation analyses and hybrid methods that bridge between atomic and coarse-grained scales