Ensemble-based methods for describing protein dynamics.

Abstract

Molecular dynamics (MD) simulation is a natural approach for studying protein dynamics, and coupled with the ideas of multiscale modeling, MD proves to be the gold standard in computational biology to investigate mechanistic details related to protein function. In principle, if MD trajectories are long enough, the ensemble of protein conformations generated allows thermodynamic and kinetic properties to be predicted. We know from experiments that proteins exhibit a high degree of fidelity in function, and that empirical kinetic models are successful in describing kinetics, suggesting that the ensemble of conformations cluster into well-defined thermodynamic states, which are frequently metastable. The experimental evidence suggest that more efficient computational models that retain only essential properties of the protein can be constructed to faithfully reproduce the relatively few observed thermodynamic states, and perhaps describe transition states if the model is sufficiently detailed. Indeed, there are many so-called ensemble-based methods that attempt to generate more complete ensembles than MD can provide by focusing on the most important driving forces through simplified representations of how elements within the protein interact. Although coarse-graining is employed in MD and other approaches, such as in elastic network models, the key distinguishing factor of ensemble-based methods is that they are meant to efficiently generate a large ensemble of conformations without solving explicit equations of motion. This review highlights three types of ensemble-based methods, illustrated by 'COREX' and the Wako-Saito-Munoz-Eaton (WSME) model, the Framework Rigidity Optimized Dynamic Algorithm (FRODA) and the distance constraint model (DCM).