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Title: How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?
Authors: Reid, Lauren M.
Guzzetti, Ileana
Svensson, Tor
Carlsson, Anna-Carin
Su, Wu
Leek, Tomas
von Sydow, Lena
Czechtizky, Werngard
Miljak, Marija
Verma, Chandra
De Maria, Leonardo
Essex, Jonathan W.
Keywords: Science::Biological sciences
Issue Date: 2022
Source: Reid, L. M., Guzzetti, I., Svensson, T., Carlsson, A., Su, W., Leek, T., von Sydow, L., Czechtizky, W., Miljak, M., Verma, C., De Maria, L. & Essex, J. W. (2022). How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?. Chemical Science, 13(7), 1957-1971.
Journal: Chemical Science
Abstract: Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) 1H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.
ISSN: 2041-6520
DOI: 10.1039/d1sc03496k
Schools: School of Biological Sciences 
Organisations: Bioinformatics Institute (A*STAR)
Department of Biological Sciences, NUS
Rights: © 2022 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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