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Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2034-9. doi: 10.1073/pnas.1414190112. Epub 2015 Feb 2.

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion.

Author information

1
Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, MI 48109; and.
2
Department of Biology, Indiana University, Bloomington, IN 47405-7000.
3
Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, MI 48109; and brookscl@umich.edu.

Abstract

Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.

KEYWORDS:

alphavirus; constant pH molecular dynamics; envelope protein; membrane fusion; pH

PMID:
25646410
PMCID:
PMC4343099
DOI:
10.1073/pnas.1414190112
[Indexed for MEDLINE]
Free PMC Article

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