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SUMMARY:Membrane-Induced Oligomerization of the Ebolavirus Matrix Protein V
 P40 as a Target for High-Throughput Drug Discovery
LOCATION:Chemistry A101
TZID:America/Denver
DTSTART:20190201T000000
UID:2026-05-04-06-00-29@natsci.colostate.edu
DTSTAMP:20260504T060029
Description:About the Seminar\nThe viral matrix protein (VP40) is crucial t
 o multiple steps of the Ebola Virus (EBOV) lifecycle\, including the regul
 ation of transcription and viral egress. In the cytosol\, VP40 monomers sp
 ontaneously dimerize and migrate to the inner-cell membrane where a reorie
 ntation causes partial penetration of the membrane and hexamer formation. 
 Further oligomerization of VP40 includes the formation of octamers vital t
 o replication\, and the filamentous self-aggregation responsible for envel
 oping the nucleocapsid and its egress. Much recent work has focused on VP4
 0 oligomerization mechanisms and detailing associated protein residues. De
 spite this\, drug discovery studies for VP40 have focused on targeting reg
 ions that many recent studies seem to suggest would not inhibit function\,
  and no further or more rigorous evidence to verify the proposed small mol
 ecules as inhibitors has been published. We therefore propose a holistic a
 pproach for high-throughput drug discovery based on small molecule inhibit
 ion of membrane attracting\, stabilizing\, and/or penetrating residues of 
 VP40\, of which all are currently hypothesized to be essential for VP40 ol
 igomerization. A combined computational-experimental workflow is detailed\
 , beginning with high-throughput virtual screening of these critical prote
 in-lipid interactions. Enhanced sampling molecular dynamics methods are de
 vised in a site-specific manner\, allowing us to then probe the difference
 s in free energies between membrane interaction of the top ligand-bound VP
 40 structures and apo-VP40. Importantly\, assays for measuring virus-like 
 particle formation and VP40 lipid-binding\, which have been previously dev
 eloped\, are adapted for additional rigor in detailing the highest affinit
 y inhibitors of VP40. 4:00 pm
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