Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment

Scientific Reports
Jan K MarzinekPeter J Bond

Abstract

Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 μs of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of me...Continue Reading

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Citations

Jun 17, 2016·Journal of Biomolecular Structure & Dynamics·Bhupesh GoyalSusheel Durani
Oct 30, 2016·Progress in Biophysics and Molecular Biology·Roland G HuberPeter J Bond
Jan 15, 2020·Antimicrobial Agents and Chemotherapy·Antonios FikatasDominique Schols
Oct 25, 2017·Journal of Computer-aided Molecular Design·Edson R A OliveiraBruno A C Horta
Jun 7, 2018·Journal of Chemical Theory and Computation·Jan K MarzinekPeter J Bond
Aug 18, 2018·The Journal of Physical Chemistry. B·Stephen J FoxChandra S Verma
Nov 17, 2021·Biochemical Society Transactions·Alzbeta Tuerkova, Peter M Kasson

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Methods Mentioned

BETA
X-ray
nuclear magnetic resonance
circular dichroism
NMR
PCA

Software Mentioned

GROMACS
MD
VMD
AA
CMAP
GROMOS
PyMol
Linux
CHARMM
CHARMM36

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