Deep mining of the protein energy landscape

Abstract

For over half a century, it has been known that protein molecules naturally undergo extensive structural fluctuations, and that these internal motions are intimately related to their functional properties. The energy landscape view has provided a powerful framework for describing the various physical states that proteins visit during their lifetimes. This Perspective focuses on the commonly neglected and often disparaged axis of the protein energy landscape: entropy. Initially seen largely as a barrier to functionally relevant states of protein molecules, it has recently become clear that proteins retain considerable conformational entropy in the “native” state, and that this entropy can and often does contribute significantly to the free energy of fundamental protein properties, processes, and functions. NMR spectroscopy, molecular dynamics simulations, and emerging crystallographic views have matured in parallel to illuminate dynamic disorder of the “ground state” of proteins and their importance in not only transiting between biologically interesting structures but also greatly influencing their stability, cooperativity, and contribution to critical properties such as allostery.

Protein conformational ensembles in function: roles and mechanisms

“…5–8 The landscape concept underscored the importance of proper physicochemical description of biological molecules—not as single structures but as ensembles with dynamic distributions that change with changes in the environment. 9–24 While the classical sequence- single structure -function dogma has been enormously useful and influential in driving the relevance of structure in biology over multiple decades, it did not portray the non-linear propagation of information which is responsible for life. 5 Different from the free energy landscape outlook, the single structure paradigm that prevailed for scores of years failed in embracing multiple states, thus in capturing biological actions, since its underlying premise has been unable to describe biological macromolecular dynamics.…”