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Principal Investigator: CAMERON F ABRAMS
Organization: DREXEL UNIVERSITY
Fiscal Year: 2023
Award: $825,050
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The HIV-1 envelope glycoprotein spike (Env) mediates viral entry into target cells. Because Env is the only
viral protein on the virion surface, it is central to the development of potential vaccines and small-molecule
entry inhibitors. Env is a uniquely flexible molecular machine, and deep understanding of its immunogenicity
and susceptibility to inhibition requires an appreciation of its atomically resolved conformational dynamics.
Structural studies using truncated, solubilized, and stabilized Env constructs have yielded detailed atomic
models of its main open and closed conformational states. Emerging structural studies of full-length Env
support identification of asymmetric closed conformations as the “default intermediate state” (DIS), revealing
details of a potentially pivotal role of quaternary asymmetry in Env conformational dynamics. At the same time,
both single-molecule FRET (smFRET) and crosslinking mass spectrometry (XL-MS) of Env suggest the
existence of at least one, sometimes dominant conformational state that has not been structurally
characterized. This “State-1” conformation nonetheless seems relevant for both immune recognition and
susceptibility to small-molecule inhibitors. We will leverage advanced Molecular Dynamics (MD) methods
including targeted MD, temperature-accelerated MD, and string method to provide atomic level models for the
opening of HIV-1 Env from closed (State 2) to open (State 3) conformational states and to identify critical
structural changes separating State-2 from the poorly understood State-1 Env. The MD simulation methods we
use will incorporate biases from multi-perspective smFRET and XL-MS, and they will in turn provide direction
for expanding the set of Env constructs used in those experiments, establishing an iterative approach that
progressively better defines transition mechanisms and State 1. An atomic-level understanding of HIV-1 Env
conformational dynamics, identification of a yet to be structurally characterized pre-triggered conformational
states, as well as the mechanism of Env activation for fusion will inform immunogen design and antiviral
therapies.
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