Studying protein-protein interactions is crucial to gaining a better understanding of processes such as metabolic control, signal transduction, and gene regulation. Many biologically important interactions occur in weak, transient complexes that are not amenable to direct experimental analysis, even if both interacting proteins can be isolated and their structures determined. Thus it is important to develop computational docking methods that, starting from the structures of component proteins, can determine the structure of their complexes with accuracy close to that obtained by X-ray crystallography. Our multistage approach to docking starts with a rigid body search that samples billions of conformations on a grid using fast Fourier transform (FFT) correlation calculations, and includes post-processing to find near-native conformations among thousands of docked structures. Our methods were among the best in the latest CAPRI docking experiment, but results are still poor for antigen-antibody and some other types of complexes. The general goal of this proposal is the development of new algorithms that will improve the accuracy and reliability of multistage docking while retaining its computational efficiency, hence enabling the use of state-of- the-art methods for a web-based docking server. We will address three problems. First, Monte Carlo-based docking programs have demonstrated that searching for optimal side chain conformations in the interface can improve results. However, Monte Carlo is not a very efficient search, and such programs are computationally too demanding to globally explore the conformational space without a priori information on the structure of the complex. To remedy this we will develop efficient docking-specific side chain search algorithms within the framework of the multistage approach. This will include the identification of "key" side chains that are most important for recognition, thereby reducing the side chains'degrees of freedom. Second, accounting for electrostatics, desolvation, hydrogen bonding, and possibly experimental constraints improves docking results, but the use of such complex scoring functions reduces the numerical advantage provided by the FFT correlation approach. We will regain this advantage by developing a multi-property 5-dimensional FFT-based algorithm that can be used with scoring functions of arbitrary complexity without added computational costs. Third, docking results are particularly poor for antibody-antigen pairs. Our preliminary data indicate that results can be substantially improved by adopting asymmetric hydrophobicity potentials that account for the biophysics of interactions in particular classes of protein-protein complexes. In the first six months of the project we set up a new version of our ClusPro server, heavily used by experimentalists, which will include recent developments. The server will be continuously updated as our new algorithms become available. In addition to providing the server, we have already started development on a modular program library specific to the docking problem that will be freely accessible.

Public Health Relevance

Studying protein-protein interactions is crucial to gaining a better understanding of processes such as metabolic control, signal transduction and gene regulation. Since many biologically important interactions occur in weak, transient complexes that are not amenable to direct experimental analysis, it is important to develop computational docking methods that, starting from the structures of component proteins, can determine the structure of their complexes with accuracy close to that obtained by X-ray crystallography. The general goal of this proposal is to further improve the accuracy of multistage docking while retaining its computational efficiency, thereby enabling the use of state-of-the-art methods in protein docking servers available to the scientific community.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061867-11
Application #
8213667
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Wehrle, Janna P
Project Start
2000-09-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
11
Fiscal Year
2012
Total Cost
$261,196
Indirect Cost
$100,460
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Bogorad, Andrew M; Xia, Bing; Sandor, Dana G et al. (2014) Insights into the architecture of the eIF2B?/?/? regulatory subcomplex. Biochemistry 53:3432-45
Bohnuud, Tanggis; Kozakov, Dima; Vajda, Sandor (2014) Evidence of conformational selection driving the formation of ligand binding sites in protein-protein interfaces. PLoS Comput Biol 10:e1003872
Mottarella, Scott E; Beglov, Dmitri; Beglova, Natalia et al. (2014) Docking server for the identification of heparin binding sites on proteins. J Chem Inf Model 54:2068-78
Kozakov, Dima; Li, Keyong; Hall, David R et al. (2014) Encounter complexes and dimensionality reduction in protein-protein association. Elife 3:e01370
Lensink, Marc F; Moal, Iain H; Bates, Paul A et al. (2014) Blind prediction of interfacial water positions in CAPRI. Proteins 82:620-32
Vajda, Sandor; Hall, David R; Kozakov, Dima (2013) Sampling and scoring: a marriage made in heaven. Proteins 81:1874-84
Golden, Mary S; Cote, Shaun M; Sayeg, Marianna et al. (2013) Comprehensive experimental and computational analysis of binding energy hot spots at the NF-ýýB essential modulator/IKKýý protein-protein interface. J Am Chem Soc 135:6242-56
Lavi, Assaf; Ngan, Chi Ho; Movshovitz-Attias, Dana et al. (2013) Detection of peptide-binding sites on protein surfaces: the first step toward the modeling and targeting of peptide-mediated interactions. Proteins 81:2096-105
Kozakov, Dima; Hall, David R; Chuang, Gwo-Yu et al. (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci U S A 108:13528-33
Kozakov, Dima; Hall, David R; Beglov, Dmitri et al. (2010) Achieving reliability and high accuracy in automated protein docking: ClusPro, PIPER, SDU, and stability analysis in CAPRI rounds 13-19. Proteins 78:3124-30

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