Flexible protein docking

As discussed above, side-chain movement or protein flexibility plays an important role in a docking process. Usually, uncertainly in side-chain placement or loop modelhng arises in protein stmctures predicted through homology modelling. Only a few docking tools consider these, like FlexE. This is a tool which considers the protein structure variations or flexibility to dock flexible ligands [22] (Fig. 4.51). 

It has options like Receptor, Ligands, GLIDE Docking, Prime Refinement, and GLIDE Redocking. This process, however, takes high computation time for good results. 

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Xu M, Lill MA (2012) Utilizing experimental data for reducing ensemble size in flexible-protein docking. J Chem Inf Model 52(1) 187-198... 

Liaison (www.schrodinger.com) Exhaustive sampling, flexible ligand-flexible protein docking Free energy Single molecule docking... 

Wong, C. (2008) Flexible hgand-flexible protein docking in protein kinase systems. Biochimica et Biophysica Acta, 1784 (1), 244-251. 

DM Lorber, BK Shoichet. Flexible ligand docking using conformational ensembles. Protein Sci 7 938-950, 1998. 

Structural properties of both AFA-PLN and WT-PLN bound to SER-CAla after reconstitution in a functional lipid bilayer environment were examined by 13C solid-state NMR.241 Chemical-shift assignments in all domains of AFA-PLN provide direct evidence for the presence of two terminal ot-helices connected by a linker region of reduced structural order that differs from previous findings on free PLN. A combination of the spectroscopic data with biophysical and biochemical data using flexible protein-protein docking simulations provides a structural basis for understanding the interaction between PLN and SERCala.244 Using a... 

Totrov, M. and Abagyan, R. Flexible protein-ligand docking by global energy optimization in internal coordinates. Proteins Suppl. 1997, 1, 215-220. 

Joseph-mccarthy, D., Thomas iv, B.E., Belmarsh, M., Moustakas, D., and Alvarez, J.C. Pharmacophore-based molecular docking to account for ligand flexibility. Proteins Struc., Func. Genet. 

B-Rao, C., Subramanian, J., Sharma, S. D. (2009) Managing protein flexibility in docking and its applications. Drug Discov Today 14, 394-400. 

Molecular dynamics (MD) should be performed for binding pockets defined mostly by side chains of flexible protein residues to generate an ensemble of binding sites. Such an ensemble can be used for subsequent docking or virtual screening in a parallel fashion. 

Schaffer, L. and Verkhivker, G. M. (1998) Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization. Proteins Struct. Fund. Gen. 33,295-310. 

D. M. Lorber and B. K. Shoichet, Protein Sci., 7, 938 (1998). Flexible Ligand Docking Using Conformational Ensembles. 

A significant work was recently presented [1] for a series of achiral FXa inhibitors, which were designed by a combination of benzamidines directed toward the EXa SI pocket. Their basic or hydrophobic substituents were directed toward the flexible S4 subsite of Factor Xa. The 3-amidinobenzyl-lH-indole-2-carboxamide scaffold as an interesting motif was also identified. A combination of X-ray structure analysis of Factor Xa and trypsin, flexible moleciflar docking, and 3D-QSAR analyses was performed to understand relevant protein-hgand... 

Sampling of the biomolecular conformations is usually performed using MD simulations or Monte Carlo methods (61, 62). The protonation state of titrateable amino acids can be treated with constant pH dynamics, QM/MM calculations, or continuum electrostatics methods (61, 62). Formation of a protein-protein encounter complex is often studied using Brownian dynamics (63). Studies of protein-protein docking involve electrostatic potential analysis and, more recently, protein flexibility models, for example normal mode analysis (64). 

Ehrlich LP, NUges M, Wade RC. The impact of protein flexibility on protein-protein docking. Proteins 2005 58 126-133. 

Cherfils J, Duquerroy S, Janin J. Protein-protein recognition analyzed by docking simulation. Proteins 1991 11 271-280. Zacharias M. Protein-protein docking with a reduced protein model accounting for side chain flexibility. Protein Sci. 2354 12 1271-1282. 

FlexX (cartan.gmd.de/FlexX) Rigid protein flexible ligand docking (incremental construction) Empirical scoring intertwined with sampling... 

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