Reliable and efficient predictions of protein interaction geometry remains an unsolved problem. Yet it is a key technology for the structural biology of the future. Our long term goal is to develop reliable protein docking prediction procedures to facilitate our structural understanding of the complex regulatory and metabolic processes that occur in living organisms, and to enable design of drugs for blocking or modifying these interactions. There are two principal bottlenecks in the current docking technology. Firstly, two proteins undergo induced conformational changes upon association, while the current methods cannot adequately deal with such flexibility. Secondly, the initial phase of the docking procedure, so called rigid body docking, is too slow to consider multiple receptor and ligand conformations. Our main goal is to overcome these bottlenecks and develop new methods to predict docking of proteins undergoing backbone deformations. The results of the first Critical Assessment of PRotein Interaction predictions (CAPRI) revealed some modest but hopeful signs in dealing with the induced fit. Here we propose to further develop the docking methodology by incorporating recent density matching algorithms, the latest achievements in small molecule docking, as well as by finding an efficient way to deal with both side-chain and backbone flexibility. To speed up the rigid body docking we will adapt a new Five Dimensional Fast Fourier Transform method for simultaneous determination of rotation and translation to protein docking. This will lead to a quick generation of trial solutions and will allow exploring multiple conformations of the interacting partners. Secondly, new trial solution re-scoring schemes and better grid potential maps used by the 5DFFT method will be developed and optimized on a benchmark of known complexes. Thirdly, better ways to treat explicit protein side-chain flexibility will be developed. Finally, we will study the phenomenon of backbone rearrangements upon association and predict multiple conformations for rigid body docking, as well as incorporate the rearrangements into refinement procedure. The emerging procedures will be applied to biological problems and tested in the CAPRI docking competition.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071872-02
Application #
6921382
Study Section
Special Emphasis Panel (ZRG1-BDMA (01))
Program Officer
Wehrle, Janna P
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$356,630
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Aznar, Nicolas; Ear, Jason; Dunkel, Ying et al. (2018) Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple. Sci Signal 11:
Schlessinger, Avner; Abagyan, Ruben; Carlson, Heather A et al. (2017) Multi-targeting Drug Community Challenge. Cell Chem Biol 24:1434-1435
Warszycki, Dawid; Rueda, Manuel; Mordalski, Stefan et al. (2017) From Homology Models to a Set of Predictive Binding Pockets-a 5-HT1A Receptor Case Study. J Chem Inf Model 57:311-321
Kufareva, Irina; Gustavsson, Martin; Zheng, Yi et al. (2017) What Do Structures Tell Us About Chemokine Receptor Function and Antagonism? Annu Rev Biophys 46:175-198
Zheng, Yi; Han, Gye Won; Abagyan, Ruben et al. (2017) Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. Immunity 46:1005-1017.e5
Gustavsson, Martin; Wang, Liwen; van Gils, Noortje et al. (2017) Structural basis of ligand interaction with atypical chemokine receptor 3. Nat Commun 8:14135
Ngo, Tony; Ilatovskiy, Andrey V; Stewart, Alastair G et al. (2017) Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat Chem Biol 13:235-242
Aznar, Nicolas; Patel, Arjun; Rohena, Cristina C et al. (2016) AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin. Elife 5:
Parsonage, Derek; Sheng, Fang; Hirata, Ken et al. (2016) X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action. J Struct Biol 194:180-90
Liu, Henry C; Goldenberg, Anne; Chen, Yuchen et al. (2016) Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach. J Pharmacol Exp Ther 359:215-29

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