Prediction of the three-dimensional structure of protein associations with components that undergo conformational deformations and partial re-structuring upon binding is a great challenge. It represents a major bottleneck in the modern structural understanding of biological function and disease. Ensemble docking emerged as a practical approach for incorporating conformational variability of a part of the system. Innovative ways to generate the ensembles using systematic omission scans and/or local relevant normal modes were developed recently by our group and tested in small ligand docking. The methods showed encouraging results in previously unsolvable cases, and are directly transferable to protein docking. In the present proposal, these methods will be extended and applied to protein docking including the most difficult docking of fully unstructured isolated or terminal peptides. Firstly, the conformational ensemble approach will be dramatically accelerated by introducing a new 4D docking procedure in which atomic models with fully flexible parts will be docked in a single run into concurrently present multiple conformation fields. Secondly, a faster and more rigorous all-atom solution refinement protocol will be applied. This protocol operates on softly restrained and fully flexible interface patches. All methods will be tested on a comprehensive induced fit benchmark for protein and peptide interactions that will be made publically available and regularly updated. Finally, the proposed docking protocol will incorporate electron microscopy (EM) data and other experimental restraints. A new damped dynamics flexible fitting method designed for EM fitting will be further developed. The new protein and peptide docking methods and multi domain EM fitting methods will be applied to solving biological problems with collaborating experimental laboratories. Structure prediction of protein and peptide complexes will lead to the discovery and characterization of new sites that can be targeted with small molecule therapeutics.

Public Health Relevance

Prediction of the three-dimensional structure of transient associations of flexible proteins and peptides represents a major bottleneck for modern structural understanding of biological function and disease. We proposed to overcome these major hurdles by using new methods for treating protein flexibility, and apply these methods to discover new targets for the development of molecular therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071872-09
Application #
8309243
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
2004-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$328,882
Indirect Cost
$116,013
Name
University of California San Diego
Department
None
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lin, Changsheng; Ear, Jason; Midde, Krishna et al. (2014) Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. Mol Biol Cell 25:3654-71
McRobb, Fiona M; Kufareva, Irina; Abagyan, Ruben (2014) In silico identification and pharmacological evaluation of novel endocrine disrupting chemicals that act via the ligand-binding domain of the estrogen receptor ?. Toxicol Sci 141:188-97
Kufareva, Irina; Katritch, Vsevolod; Participants of GPCR Dock 2013 et al. (2014) Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure 22:1120-39
Chen, Yu-Chen; Totrov, Max; Abagyan, Ruben (2014) Docking to multiple pockets or ligand fields for screening, activity prediction and scaffold hopping. Future Med Chem 6:1741-55
Kennedy, Dylan P; McRobb, Fiona M; Leonhardt, Susan A et al. (2014) The second extracellular loop of the adenosine A1 receptor mediates activity of allosteric enhancers. Mol Pharmacol 85:301-9
Gabrielsen, Mari; Kurczab, Rafa?; Siwek, Agata et al. (2014) Identification of novel serotonin transporter compounds by virtual screening. J Chem Inf Model 54:933-43
Acharya, Chayan; Kufareva, Irina; Ilatovskiy, Andrey V et al. (2014) PeptiSite: a structural database of peptide binding sites in 4D. Biochem Biophys Res Commun 445:717-23
McRobb, Fiona M; SahagĂșn, Virginia; Kufareva, Irina et al. (2014) In silico analysis of the conservation of human toxicity and endocrine disruption targets in aquatic species. Environ Sci Technol 48:1964-72
Kufareva, Irina; Lenoir, Marc; Dancea, Felician et al. (2014) Discovery of novel membrane binding structures and functions. Biochem Cell Biol 92:555-63
Tan, Qiuxiang; Zhu, Ya; Li, Jian et al. (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341:1387-90

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