Journal article
Roles of conserved tryptophans in trimerization of HIV‐1 membrane‐proximal external regions: Implications for virucidal design via alchemical free‐energy molecular simulations
Proteins, structure, function, and bioinformatics, v 86(7), pp 707-711
Jul 2018
PMID: 29633345
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The Dual‐Action Virolytic Entry Inhibitors, or “DAVEI's,” are a class of recombinant fusions of a lectin, a linker polypeptide, and a 15‐residue fragment from the membrane‐proximal external region (MPER) of HIV‐1 gp41. DAVEI's trigger rupture of HIV‐1 virions, and the interaction site between DAVEI MPER and HIV‐1 lies in the gp41 component of the envelope glycoprotein Env. Here, we explore the hypothesis that DAVEI MPER engages Env gp41 in a mode structurally similar to a crystallographic MPER trimer. We used alchemical free‐energy perturbation to assess the thermodynamic roles of each of the four conserved tryptophan residues on each protomer of MPER3. We found that a W666A mutation had a large positive
ΔΔG for all three protomers, while W672A had a large positive
ΔΔG for only two of the three protomers, with the other tryptophans remaining unimportant contributors to MPER3 stability. The protomer for which W672 is not important is unique in the placement of its W666 sidechain between the other two protomers. We show that the unique orientation of this W666 sidechain azimuthally rotates its protomer away from the orientation it would have if the trimer were symmetric, resulting in the diminished interaction of this W672 with the rest of MPER3. Our findings are consistent with our previous experimental study of W‐to‐A mutants of DAVEI. This suggests that DAVEI MPER may engage HIV‐1 Env to form a mixed trimer state in which one DAVEI MPER forms a trimer by displacing a more weakly interacting protomer of the endogenous Env MPER trimer.
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Details
- Title
- Roles of conserved tryptophans in trimerization of HIV‐1 membrane‐proximal external regions: Implications for virucidal design via alchemical free‐energy molecular simulations
- Creators
- Steven T Gossert - Department of Chemical and Biological Engineering, 3141 Chestnut StBibek Parajuli - Drexel University College of MedicineIrwin Chaiken - Drexel University College of MedicineCameron F Abrams - Drexel University College of Medicine
- Publication Details
- Proteins, structure, function, and bioinformatics, v 86(7), pp 707-711
- Publisher
- Wiley
- Number of pages
- 5
- Grant note
- National Institutes of Health (R01 GM115249) National Science Foundation (ACI‐1548562)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemical and Biological Engineering
- Web of Science ID
- WOS:000435812700002
- Scopus ID
- 2-s2.0-85048727883
- Other Identifier
- 991014969767304721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics