On the Helix Propensity in Generalized Born Solvent Descriptions of Modeling the Dark Proteome
USAMRIID Frederick United States
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Intrinsically disordered protein regions that populate the so-called Dark Proteomeoffer challenging benchmarks of conformational sampling methods and their all-atom forcefields plus solvent descriptions to accurately model structural transitions on a multidimensionalenergy landscape. This work explores the application of parallel tempering methods withimplicit solvent models as a computational framework to capture the conformational ensemble ofan intrinsically disordered peptide derived from the Ebola virus protein VP35. A recent X-raycrystallographic study reported a protein-peptide interface where the VP35 peptide underwent afolding transition from a disordered form to a helix--turn-helix fold upon molecular associationwith the Ebola protein NP. An assessment is provided of the accuracy of two generalized Bornsolvent models GBMV2 and GBSW2 using the CHARMM force field and applied withtemperature-based replica exchange dynamics to calculate the disorder propensity of the peptideand its probability density of states in a continuum solvent. A further comparison is presented ofapplying an explicitimplicit solvent hybrid replica exchange simulation of the peptide.