Towards complete descriptions of the free-energy landscapes of proteins

Abstract

In recent years increasingly detailed information about the structures and dynamics of protein molecules has been obtained by innovative applications of experimental techniques, in particular nuclear magnetic resonance spectroscopy and protein engineering, and theoretical methods, notably molecular dynamics simulations. In this article we discuss how such approaches can be combined by incorporating a wide range of different types of experimental data as restraints in computer simulations to provide unprecedented detail about the ensembles of structures that describe proteins in a wide variety of states from the native structure to highly unfolded species. Knowledge of these ensembles is beginning to enable the complete free-energy landscapes of individual proteins to be defined at atomic resolution. This strategy has provided new insights into the mechanism by which proteins are able to fold into their native states, or by which they fail to do so and give rise to harmful aggregates that are associated with a wide range of debilitating human diseases.