Optimizing hydrogen-deuterium exchange ensemble reweighting using candidate ensembles of calmodulin

Abstract

Hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments provide unique insights into protein structural dynamics in solution, but this technique is practically restricted to peptide-level resolution. In contrast, molecular dynamics (MD) simulations allow the exploration of a protein’s conformational landscape with atomistic resolution. However, sampling and timescale limitations may mean that the resulting conformations inaccurately reflect the protein’s behavior in solution. A novel maximum entropy reweighing approach, HDXer, was recently developed to (1) predict H/D exchange from an ensemble of generated conformations and (2) reweight individual structures of the modeled ensemble such that the ensemble better conforms with HDX-MS data using a maximum entropy approach.