[R01] Combining Molecular Simulations and Biophysical Methods to Characterize Conformational Dynamics of the HIV-1 Envelope Glycoprotein

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2028-06-30

Importo max: 790.210 EUR

Paese: US

Descrizione

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. Istituzione: DREXEL UNIVERSITY PI: CAMERON F ABRAMS, WALTHER H MOTHES, JOSEPH G SODROSKI Progetto: 5R01AI178833-04

Settori: National Institute of Allergy and Infectious Diseases

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