On the Helix Propensity in Generalized Born Solvent Descriptions of Modeling the Dark Proteome.

Mark A Olson

doi:10.3389/fmolb.2017.00003

Abstract

Intrinsically disordered proteins that populate the so-called “Dark Proteome” offer challenging benchmarks of atomistic simulation methods to accurately model conformational transitions on a multidimensional energy landscape. This work explores the application of parallel tempering with implicit solvent models as a computational framework to capture the conformational ensemble of an intrinsically disordered peptide derived from the Ebola virus protein VP35. A recent X-ray crystallographic study reported a protein-peptide interface where the VP35 peptide underwent a folding transition from a disordered form to a helix-β-turn-helix topological fold upon molecular association with the Ebola protein NP. An assessment is provided of the accuracy of two generalized Born solvent models (GBMV2 and GBSW2) using the CHARMM force field and applied with temperature-based replica exchange dynamics to calculate the disorder propensity of the peptide and its probability density of states in a continuum solvent. A further comparison is presented of applying an explicit/implicit solvent hybrid replica exchange simulation of the peptide to determine the effect of modeling water interactions at the all-atom resolution.

Highlights

The large conformational heterogeneity and rapid dynamic transitions of intrinsically disordered peptides and proteins (IDPs) present a challenge to experimental boundaries in characterizing their functional form on rugged energy landscapes (Wright and Dyson, 1999, 2005)
The work presented here examined the application of temperature-based replica exchange simulations with different sampling methods and solvent descriptions of modeling an intrinsically disorder 28residue peptide from the Ebola virus protein VP35
The Xray crystallographic determination of the VP35 peptide bound to Ebola NP reports a helix-β-turn-helix fold of roughly 40% helical structure, whereas from circular dichroism (CD) experiments in free solution the peptide is unstructured

Summary

Introduction

The large conformational heterogeneity and rapid dynamic transitions of intrinsically disordered peptides and proteins (IDPs) present a challenge to experimental boundaries in characterizing their functional form on rugged energy landscapes (Wright and Dyson, 1999, 2005). Recent experimental studies have begun to unravel the interplay between “ordered chaos” of IDPs and their kinetic transition to a topological funnel of folded states (Arai et al, 2015). The contemporary view of this dynamic process is one that occurs by either an “induced-fit” of the IDP upon molecular association with a protein target or by target “fly casting” of a prefolded state in the disordered conformational ensemble of the IDP (see, e.g., Shoemaker et al, 2000; Arai et al, 2015).

Methods

Results

Conclusion