Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts

Characterization of Glycosylation Profiles of the HIV Envelope Protein Cesar Lopez 1 , Jianhui Tian 2 , Cynthia Derdeyn 3 , Abraham Pinter 4 , Bette Korber 1 , Gnana Gnanakaran 1 . 1 Los Alamos National Labs, Los Alamos, NM, USA, 2 Oakridge National Labs, Oakridge, TN, USA, 3 Emory University, Atlanta, GA, USA, 4 Rutgers University, Newark, NJ, USA. Heavy glycosylation of the envelope (Env) surface subunit, gp120, is a key adaptation of HIV-1, however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. In general, glycosylation can stabilize protein conformation, accelerate protein folding, promote secondary structure formation, reduce protein aggregation, shield hydrophobic surfaces, promote disulfide pairing, and increase folding cooperativity. It is well known that gp120 can accommodate a remarkable heterogeneity in terms of the number and location of glycosylation sites. The network of glycans on gp120 is of particular interest with regards to vaccine design, because the glycans both serve as targets for many classes of broadly neutralizing antibodies, and contribute to patterns of immune evasion and escape during HIV-1 infection. We will present results from two separate computational studies. In the first study, large-scale all-atom and coarse-grained molecular dynamics simulations have been used to characterize the effect of glycosylation on the Env Trimer (SOSIP). We identify the key glycosylations that contribute to the stability of Env spike and quantify their energetic contributions. In the second study, we consider an antigenic peptide fragment from the disulfide bridge-bounded region spanning the V1-V2 hyper-variable domains of HIV-1 gp120. We used replica exchange molecular dynamics simulations to investigate how glycosylation influences its conformation and stability. We characterize how glycosylation can stabilize pre-existing conformations of this peptide construct, reduced its propensity to adopt other secondary structures, and provided resistance against thermal unfolding. These studies help to overcome the limited knowledge of how glycosylation and disulfide bonds affect the conformation and dynamics of short intrinsically disordered peptides complicates the design of immunogenic peptides. We will show how the sequence, structural and thermodynamic profiles of glycosylation of gp120 can aid in the design of glycopeptide-based immunogens.

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