Probing the mechanism of pH-induced large-scale conformational changes in dengue virus envelope protein using atomistic simulations.

Biophysical Journal
Meher K PrakashMichele Parrinello

Abstract

One of the key steps in the infection of the cell by dengue virus is a pH-induced conformational change of the viral envelope proteins. These envelope proteins undergo a rearrangement from a dimer to a trimer, with large conformational changes in the monomeric unit. In this article, metadynamics simulations were used to enable us to understand the mechanism of these large-scale changes in the monomer. By using all-atom, explicit solvent simulations of the monomers, the stability of the protein structure is studied under low and high pH conditions. Free energy profiles obtained along appropriate collective coordinates demonstrate that pH affects the domain interface in both the conformations of E monomer, stabilizing one and destabilizing the other. These simulations suggest a mechanism with an intermediate detached state between the two monomeric structures. Using further analysis, we comment on the key residue interactions responsible for the instability and the pH-sensing role of a histidine that could not otherwise be studied experimentally. The insights gained from this study and methodology can be extended for studying similar mechanisms in the E proteins of the other members of class II flavivirus family.

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Citations

Dec 1, 2012·Journal of Molecular Modeling·Carlos A Fuzo, Léo Degrève
Sep 4, 2012·Biochimica Et Biophysica Acta·Kshatresh Dutta DubeyRajendra Prasad Ojha
Jul 28, 2012·Biochemical and Biophysical Research Communications·Dmitry I OsolodkinNikolay S Zefirov
Mar 13, 2014·Biophysical Journal·Aurélie GouronHelene Jamet
Aug 24, 2013·Journal of Biomolecular Structure & Dynamics·Carlos Alessandro Fuzo, Léo Degrève
Apr 29, 2016·PLoS Computational Biology·Tatiana MaximovaAmarda Shehu
Dec 8, 2015·Journal of Virology·Adolfo H MoraesAna P Valente
Jun 12, 2020·Methods : a Companion to Methods in Enzymology·Roland G HuberPeter J Bond
Feb 20, 2021·Virus Research·Debajit DeyS Saif Hasan
Nov 18, 2015·Journal of Chemical Theory and Computation·Koichi Tamura, Shigehiko Hayashi
Sep 14, 2013·The Journal of Physical Chemistry. B·Andrew J IlottMark R Wilson

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