Structural Bioinformatics Core Section
Description of Research Program
The Structural Bioinformatics Core Section (SBIS) seeks to apply the tools of computational biology and structural bioinformatics to the design of an effective HIV-1 vaccine. Over the last few years, these tools have met with growing success when applied to a wide range of problems, including protein design, protein-structure prediction, enzyme design, and drug design. Our goal is to utilize available state-of-the-art structural bioinformatics tools, as well as to develop novel methodologies, as part of a collaborative effort—within the Vaccine Research Center, with other intramural portions of the National Institutes of Health, and extramurally—to assist in vaccine design against HIV-1 and other viruses.
The efforts of the SBIS can be divided into three areas:
- Application of computational techniques to structure-based immunogen design. Specifically, a variety of techniques can be used to focus the immune response toward target epitopes and away from undesirable, often immunoprominent, regions, through an iterative process of structure-based design, immunogenic evaluation, computational manipulation, and immunogen redesign. This process takes advantage of other skill sets resident within the Virology laboratory, specifically the ability of the Structural Biology Section to provide atomic-level details on the target epitope, and of the Vector core to evaluate immunogens. We expect this strategy of rational immunogen design to lead to the elicitation of antibodies that broadly neutralize a diverse range of HIV-1 isolates. The direct rational structure-based design of antibodies is also of interest to the SBIS.
- Efforts to enhance protein crystallization and structural analysis through the use of computational tools. The solution of crystal structures and in-depth structural analysis play a pivotal role in current efforts for rational immunogen design. Often, a significant amount of structural information exists about an important biological system (e.g., for protein subunits or from cryo-electron tomography), though the central biological target resists atomic-level structural analysis (e.g., the functional viral spike of HIV-1). Computational biology can serve as a bridge between these other sources of information and the design of appropriate crystallization constructs, to enable atomic-level analysis of a particular target. Moreover, once the structure of a particular target is determined, computational biology can assist in the analysis of the structure, to extract its full biological meaning.
- Computationally-assisted design of probes for analysis of sera and isolation of monoclonal antibodies. An understanding of the serum responses of both HIV-1-infected individuals and vaccines should assist in the development of an effective HIV-1 vaccine. Computational design can assist in the development of antigenically specific probes useful in analyzing the neutralizing activity of sera and in deciphering the HIV-1 elements recognized by both binding and neutralizing antibodies. Such an understanding provides critical in vivo feedback for the iterative structure-based improvement of immunogens.
Recent progress in the field has provided encouragement that development of a vaccine for HIV-1 is possible. By combining the power and efficiency of computation with the plethora of information encrypted in protein structures, SBIS can play a central role in the vaccine design process.
Vaccine Design Process
Structural Bioinformatics Core Section 2011
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Left to Right: Top row: Jiang Zhu, Ivelin Georgiev, Gwo-Yu Chuang,
Bottom row: Lawrence Shapiro, Jennifer Burke, Peter Kwong, Zhenhai Zhang |
Selected Publications
19. Zhu J, O'Dell S, Ofek G, Pancera M, Wu X, Zhang B, Zhang Z; NISC Comparative Sequencing Program, Mullikin JC, Simek M, Burton DR, Koff WC, Shapiro L, Mascola JR, Kwong PD. (2012). Somatic Populations of PGT135-137 HIV-1-Neutralizing Antibodies Identified by 454 Pyrosequencing and Bioinformatics. Front Microbiol. Epub 2012 Sep 11.
SBIS contribution: Jiang Zhu carried out a benchmark study of the 454-pyrosequencing-induced sequence variation using plasmids of 10 HIV-1 broadly neutralizing antibodies as input. He then investigated the somatic variation of three neutralizing antibodies (PGT135–137) that target an epitope containing an N-linked glycan at residue 332 on HIV-1 gp120 by combing 454 pyrosequencing and bioinformatics analysis. The results indicate that the sequence diversity observed with the PGT135-137 antibodyome was notably higher than observed with the 10-plasmid controls, suggesting that this diversity results primarily from somatic maturation.
18. Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, Decamp AC, Carrico C, Menis S, Magaret CA, Ahmed H, Juraska M, Chen L, Konopa P, Nariya S, Stoddard JN, Wong K, Zhao H, Deng W, Maust BS, Bose M, Howell S, Bates A, Lazzaro M, O'Sullivan A, Lei E, Bradfield A, Ibitamuno G, Assawadarachai V, O'Connell RJ, Desouza MS, Nitayaphan S, Rerks-Ngarm S, Robb ML, McLellan JS, Georgiev I, Kwong PD, Carlson JM, Michael NL, Schief WR, Gilbert PB, Mullins JI, Kim JH. (2012) Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature, Epub Sep 10.
SBIS contributions: Generation of an antibody contact residue database, and structural analysis of signature residues within V2 of HIV-1 Env.
17. Kong R, Li H, Georgiev I, Changela A, Bibollet-Ruche F, Decker JM, Rowland-Jones SL, Jaye A, Guan Y, Lewis GK, Langedijk JP, Hahn BH, Kwong PD, Robinson JE, Shaw GM. (2012) Epitope mapping of broadly neutralizing human HIV-2 monoclonal antibodies. J Virol. Epub Aug 29.
SBIS Contributions: Structural modeling facilitated the analysis of the epitopes targeted by different groups of broadly neutralizing human HIV-2 monoclonal antibodies.
16. Chuang GY, Boyington JC, Joyce MG, Zhu J, Nabel GJ, Kwong PD, Georgiev I. (2012) Computational Prediction of N-linked Glycosylation Incorporating Structural Properties and Patterns. Bioinformatics. 28(17):2249-55. Epub Jul 10.
SBIS Contributions: Development of a Random Forest classifier trained on structural properties and residue patterns to determine the glycan occupancy of consensus N-linked glycosylation sequons.
15. Bar KJ, Tsao CY, Iyer SS, Decker JM, Yang Y, Bonsignori M, Chen X, Hwang KK, Montefiori DC, Liao HX, Hraber P, Fischer W, Li H, Wang S, Sterrett S, Keele BF, Ganusov VV, Perelson AS, Korber BT, Georgiev I, McLellan JS, Pavlicek JW, Gao F, Haynes BF, Hahn BH, Kwong PD, Shaw GM. Early Low-Titer Neutralizing Antibodies Impede HIV-1 Replication and Select for Virus Escape. PLoS Pathog. May;8(5):e1002721.
SBIS contribution: Structural modeling of HIV-1 escape mutations was used in the analysis of the putative epitopes targeted by early low-titer neutralizing antibodies in sera from three subjects.
14. Doria-Rose NA, Georgiev I, O'Dell S, Chuang GY, Staupe RP, McLellan JS, Gorman J, Pancera M, Bonsignori M, Haynes BF, Burton DR, Koff WC, Kwong PD, Mascola JR. (2012) A Short Segment of the HIV-1 gp120 V1/V2 Region Is a Major Determinant of Resistance to V1/V2 Neutralizing Antibodies. J. Virol. Epub May 23.
SBIS contribution: A combination of sequence- and structure-based analysis of strain-specific resistance to antibody PG9 revealed a common mechanism of HIV-1 resistance to an entire class of V1/V2-directed broadly neutralizing antibodies.
13. Kwon YD, Finzi A, Wu X, Dogo-Isonagie C, Lee LK, Moore LR, Schmidt SD, Stuckey J, Yang Y, Zhou T, Zhu J, Vicic DA, Debnath AK, Shapiro L, Bewley CA, Mascola JR, Sodroski JG, Kwong PD. (2012) Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci U S A. 109(15):5663-8. Epub Mar 26.
SBIS contribution: The structural difference between the unliganded gp120 core and previously determined antibody-bound gp120 structures were analyzed. In the analysis, amino acids of gp120 were divided into three sets: inner domain, outer domain and bridging sheeet with the backbone RMSD calcaculated for each set. This analysis revealed that the unliganded gp120 closely resembles the gp120 conformation in CD4-bound state. The residue-based structural deviation was also calculated after structural superposition of two gp120s and displayed on the molecular surface.
12. Hansman GS, Taylor DW, McLellan JS, Smith TJ, Georgiev I, Tame JR, Park SY, Yamazaki M, Gondaira F, Miki M, Katayama K, Murata K, Kwong PD. (2012) Structural basis for broad detection of genogroup II noroviruses by a monoclonal antibody that binds to a site occluded in the viral particle. J Virol, 86(7), 3635-46, Epub 2012 Jan 25.
SBIS contribution: Sequence conservation and structural analyses assisted in evaluating the properties of an epitope targeted by a broad monoclonal antibody against genogroup II noroviruses.
11. McLellan JS, Pancera M, Carrico C, Gorman J, Julien JP, Khayat R, Louder R, Pejchal R, Sastry M, Dai K, O'Dell S, Patel N, Shahzad-Ul-Hussan S, Yang Y, Zhang B, Zhou T, Zhu J, Boyington JC, Chuang GY, Diwanji D, Georgiev I, Do Kwon Y, Lee D, Louder MK, Moquin S, Schmidt SD, Yang ZY, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Burton DR, Koff WC, Walker LM, Phogat S, Wyatt R, Orwenyo J, Wang LX, Arthos J, Bewley CA, Mascola JR, Nabel GJ, Schief WR, Ward AB, Wilson IA, Kwong PD. (2011) Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature. 480(7377):336-43. Epub Nov 23.
SBIS contribution: Conformation constructions of missing V1 loop and V2 loop in the crystal structures and attached glycans. Development of an in-silico Arginine Scanning algorithm to map out the contact surface of PG16 paratope. Analysis of the average surface electrostatic potential at the contact interface between the antibodies and V1/V2 domain. Structure analysis in the context of the effects on neutralization of known V1V2 mutations. Sequence/structural analysis of HIV-1 strains not containing a glycan at residue 156.
10. Hansman GS, Shahzad-Ul-Hussan S, McLellan JS, Chuang GY, Georgiev I, Shimoike T, Katayama K, Bewley CA, Kwong PD. (2011) Structural basis for norovirus inhibition and fucose mimicry by citrate. J Virol. 86(1):284-92. Epub Oct 26.
SBIS contribution: Computational docking predicted other proteins with similar fucose/citrate mimicry as observed in norovirus P domain.
9. Kong R, Li H, Bibollet-Ruche F, Decker JM, Zheng NN, Gottlieb GS, Kiviat NB, Salif Sow P, Georgiev I, Hahn BH, Kwong PD, Robinson JE, Shaw GM. (2011) Broad and Potent Neutralizing Antibody Responses Elicited in Natural HIV-2 Infection. J Virol. Epub Oct 26.
SBIS contribution: Sequence analysis revealed that a diverse set of HIV-1 strains had a significantly higher number of potential V4 glycosylation sites as compared to the panel of HIV-2 strains used in this study, suggesting that the V4 region in HIV-2 may be more accessible to antibodies and a better neutralization target than in HIV-1 primary strains.
8. Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O'Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose N, Connors M; NISC Comparative Sequencing Program, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR. (2011). Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science. 333(6049):1593-602. Epub Aug 11th
SBIS contribution: Structural bioinformatics of antibodyomes. A comprehensive computational pipeline was developed to process and to analyze expressed antibody sequences obtained by 454 pyrosequencing. With raw sequencing data as input, grid analysis allows potentially neutralizing sequences to be selected based on critical characteristics such as maturation degree and sequence identity to a known antibody; "cross-donor phylogenetic" analysis allows VRC01-like antibodies to be identified and maturation intermediates to be calculated; and genome-wide CDR-H3 analysis identifies maturation pathways.
7. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O'Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori D, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF. (2011). Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors. J Virol. 85(19):9998-10009. Epub Jul 27th
SBIS contribution: Evaluation of antibody sequences for structural compatibility. Amino acid sequences of CH01-CH04 antibodies were threaded onto antibody structures and their sequence/structure compatibilities were evaluated using statistical potentials, as an indicator of whether or not the CH01-CH04 adopts a structure similar to other V2-directly broadly neutralizing antibodies.
6. Kwong PD, Shapiro L. (2011). Vaccine design reaches the atomic level. Sci Transl Med.13;3(91):91ps29.
SBIS contribution: Structure-based vaccine design is progressing on many fronts, including the creation of an effective meningococcus B vaccine, which we review here.
5. Sastry M, Xu L, Georgiev I, Bewley CA, Nabel GJ, Kwong PD. (2011). Mammalian Production of an Isotopically Enriched Outer Domain of the HIV-1 gp120 Glycoprotein for NMR Spectroscopy. JBNMR. 50(3), 197-207 Epub Jun 12th.
SBIS contribution: Mass spectrometry data of isotopically labeled proteins were complex and difficult to decipher: theoretical analysis enabled the isotope content to be estimated at an average of over 80% 15N and 15N/13C incorporation for HIV‐1 gp120 outer domain produced in adenovirus vector‐based mammalian expression system.
4. Hansman GS, Biertümpfel C, Georgiev I, McLellan JS, Chen L, Zhou T, Katayama K, Kwong PD. (2011). Crystal Structures of GII.10 and GII.12 Norovirus Protruding Domains in Complex with Histo-Blood Group Antigens Reveal Details for a Potential Site of Vulnerability. J Virol. 85(13):6687-701. Epub Apr 27th.
SBIS contribution: Examination of norovirus genogroup GII sequence conservation, combined with analysis of HBGA‐bound GII P domain crystal structures, revealed a potential site of viral vulnerability at the base of the HBGA recognition site.
3. Changela A, Wu X, Yang Y, Zhang B, Zhu J, Nardone GA, O’Dell S, Pancera M, Gorny MK, Phogat S, Robinson JE, Stamatatos L, Zolla-Pazner S, Mascola JR, Kwong PD. (2010). Crystal structure of human antibody 2909 reveals conserved features of quaternary-specific antibodies that potently neutralize HIV-1. J Virol. 85(6):2524-35. Epub Dec 29th. PDB: 3piq.
SBIS contribution: Bioinformatics analysis revealed that the 2909 CDR‐H3 loop is a rare structural motif among all protein structures and that several anti‐HIV‐1 antibodies, such as 447‐52D and Z13e1, have structurally similar CDR H3 regions.
2. Zhou T, Georgiev I, Wu X, Yang Z, Dai K, Finzi A, Kwon YD, Scheid J, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD. (2010). Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01. Science. 329 (5993), 811-817 Epub July 8.
SBIS contribution: Bioinformatics analysis of the commonality of VRC01 structure and sequence features helped identify possible barriers to elicitation of VRC01‐like broadly neutralizing antibodies.
1. Pancera M, McLellan JS, Wu X, Zhu J, Changela A, Schmidt SD, Yang Y, Zhou T, Phogat S, Mascola JR, Kwong PD. (2010). Crystal structure of PG16 and chimeric dissection with somatically related PG9: Structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1. J Virol. 84, 8098-8110 Epub June 10.
SBIS contribution: CryoEM‐based modeling technique was used to refine PG16 CDR‐H3 loop in low-resolution X‐ray density and bioinformatics analysis identified close structural homologs of PG16 CDR‐H3 loop from unrelated proteins in protein databank.
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