Normal Mode Analysis Techniques in Structural Biology

Abstract

Abstract The dynamic simulation of macromolecular systems with biologically relevant sizes and time scales is critical for understanding macromolecular function. In this context, normal mode analysis (NMA) approximates the complex dynamical behaviour of a macromolecule as a simple set of harmonic oscillators vibrating around a given equilibrium conformation. This technique, originated from classical mechanics, was first applied to investigate the dynamical properties of small biological systems more than 30 years ago. During this time, a wealth of evidence has accumulated to support NMA as a successful tool for simulating macromolecular motions at extended length scales. Today, NMA combined with coarse‐grained representations has become an efficient alternative to molecular dynamics simulations for studying the slow and large‐amplitude motions of macromolecular machines. Interesting insights into these systems can be obtained very quickly with NMA to characterise their flexibility, to predict the directions of their collective conformational changes, or to help in the interpretation of experimental structural data. The recently developed methods and applications of NMA together with an introduction of the underlying theory will be briefly reviewed here. Key Concepts: NMA computes all motions around an equilibrium conformation (normal modes). Normal modes are orthogonal displacement vectors with an associated frequency. The collective functional motions of the macromolecules are well described by lowest frequency modes. NMA inexpensive and accurately simulates the slow and large‐amplitude motions of biomolecules, but local reorganisations and the absolute time scale or amplitude of the motions are poorly predicted. NMA can be used to characterise macromolecular flexibility, to predict the directions of collective conformational changes, and to interpret structural experimental data.