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.
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.
|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|
|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|
|Gustavsson, Martin; Wang, Liwen; van Gils, Noortje et al. (2017) Structural basis of ligand interaction with atypical chemokine receptor 3. Nat Commun 8:14135|
|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|
|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|
|Liu, Henry C; Jamshidi, Neema; Chen, Yuchen et al. (2016) An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network. J Biol Chem 291:19474-86|
|Leach, Katie; Gregory, Karen J; Kufareva, Irina et al. (2016) Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor. Cell Res 26:574-92|
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