Revealing the Mechanism for Conformational Changes from Structurally Rich Ensembles

Abstract

Conformational changes in proteins are essential to their biological functions, from allosteric regulation to signal propagation. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the mechanisms underlying these processes highly elusive. Here, applying an innovative combination of Principal Component Analysis (PCA) of experimental ensembles and coarse-grained simulations [1], we dissect the essential motions orchestrating biological functions for the highly studied ion channel GLIC. This prokaryotic protein, which has been solved in different functional states along the gating cycle, is a prototype for the Pentameric Ligand-Gated Ion Channels (PLGICs) that mediate synaptic communication. We show how the Principal Components (PCs) of the GLIC ensemble decode the core motions common to all the current structures, providing mathematical reaction coordinates to cluster them and reveal clearly the interconnecting pathways. Modeling GLIC as an elastic network in a Langevin simulation, we generate smooth trajectories between end-points that visit spontaneously multiple intermediate states along the transition, providing a realistic description of the mechanism. Finally, by direct analysis of the correlated motions along the dominant PCs we unveil an elegant mechanism to propagate information from the binding site throughout the protein [2]. Our approach provides a powerful and general theoretical framework to study conformational changes and synthetize the rich structural information deposited currently in the Protein Data Bank.1.Orellana L., Yoluk O., Orozco M., Lindahl E. Revealing conformational transition pathways by analysis of structurally rich X-ray ensembles and coarse-grained simulations (2015) (submitted)2.Fenwick R.B.∗, Orellana L.∗, Esteban-Martin S., Orozco M., Salvatella X. Correlated motions are a fundamental property of beta-sheets. Nature Communications (2014); 5: 4070. http://dx.doi.org/10.1038/ncomms5070 ∗ Shared First Authorship