Abstract

The solution of crystal structures and in-depth structural analysis play a pivotal role in current efforts for rational antibody-based vaccine design. However, the structures for many important targets, such as viral surface proteins, haven proven extremely difficult to determine using traditional methods such as protein crystallization and NMR. This presents a significant obstacle to structure-based vaccine design efforts, which rely heavily on the availability of high-quality atomic-level structural information. Computational tools that allow modeling and molecular dynamics simulation of proteins at different levels of structural detail can provide a rational basis for the molecular design of proteins more suitable for crystallization, thus enabling atomic-level characterization of otherwise evasive targets. Moreover, once the structure of a particular target is determined, computational tools can also assist in structural analysis, to help extract biologically meaningful data and to guide new experimental efforts. Here we develop and utilize computational tools to assist in protein crystallization and structural analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICAI005112-08
Application #
9551941
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Xu, Kai; Acharya, Priyamvada; Kong, Rui et al. (2018) Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. Nat Med 24:857-867
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Kisalu, Neville K; Idris, Azza H; Weidle, Connor et al. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat Med 24:408-416
Kwong, Peter D; Mascola, John R (2018) HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity 48:855-871
Xu, Ling; Pegu, Amarendra; Rao, Ercole et al. (2017) Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science 358:85-90
Curreli, Francesca; Kwon, Young Do; Belov, Dmitry S et al. (2017) Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120. J Med Chem 60:3124-3153
Liu, Qingbo; Acharya, Priyamvada; Dolan, Michael A et al. (2017) Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer. Nat Struct Mol Biol 24:370-378
Kwong, Peter D (2017) What Are the Most Powerful Immunogen Design Vaccine Strategies? A Structural Biologist's Perspective. Cold Spring Harb Perspect Biol :

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