Multiscale Computational Microscopy of HIV-1

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ABSTRACT The human immunodeficiency virus 1 (HIV-1) is the RNA retrovirus that causes acquired immunodeficiency syndrome (AIDS), a disease that has killed over 40 million people worldwide and infected more than twice that. Continued high infection rates has made understanding of HIV biology and vaccines a high priority. A key molecule involved in both infection and vaccine efforts is the HIV-1 Envelope protein (Env). Experimental structural biology techniques have characterized the basic structure of Env, but they are unable to provide details about the extensive N-linked glycan shield nor inform on the flexibility and dynamics of Env. In this proposal, we envision using all-atom molecular dynamics simulations as a `computational microscope,' to provide insights into the dynamics of Env that are unattainable with current experimental techniques. Together with top flight experimentalists, we will develop and simulate a series of models to explore the dynamics of Env as well as its interactions with co-receptors and the cell glycocalyx, in unprecedented detail. In addition, we will use advanced simulation techniques to optimize immunogen design as well as provide critical information about hitherto unseen druggable sites in Env.