Insights into Phosphorylation-Induced Protein Allostery and Conformational Dynamics of Glycogen Phosphorylase via Integrative Structural Mass Spectrometry and In Silico Modeling

Significance Many proteins that perform important biological functions are completely or partially disordered under physiological conditions. Molecular dynamics simulations could be a powerful tool for the structural characterization of such proteins, but it has been unclear whether the physical models (force fields) used in simulations are sufficiently accurate. Here, we systematically compare the accuracy of a number of different force fields in simulations of both ordered and disordered proteins, finding that each force field has strengths and limitations. We then describe a force field that substantially improves on the state-of-the-art accuracy for simulations of disordered proteins without sacrificing accuracy for folded proteins, thus broadening the range of biological systems amenable to molecular dynamics simulations.

Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used hereto provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.