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Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts
11
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.