Side-chain flexibility in proteins upon ligand binding Export

@article{citeulike:934387, abstract = {Ligand binding may involve a wide range of structural changes in the receptor protein, from hinge movement of entire domains to small side-chain rearrangements in the binding pocket residues. The analysis of side chain flexibility gives insights valuable to improve docking algorithms and can provide an index of amino-acid side-chain flexibility potentially useful in molecular biology and protein engineering studies. In this study we analyzed side-chain rearrangements upon ligand binding. We constructed two non-redundant databases (980 and 353 entries) of ldquopairedrdquo protein structures in complexed (holo-protein) and uncomplexed (apo-protein) forms from the PDB macromolecular structural database. The number and identity of binding pocket residues that undergo side-chain conformational changes were determined. We show that, in general, only a small number of residues in the pocket undergo such changes (e.g., sim85\% of cases show changes in three residues or less). The flexibility scale has the following order: Lys \> Arg, Gln, Met \> Glu, Ile, Leu \> Asn, Thr, Val, Tyr, Ser, His, Asp \> Cys, Trp, Phe; thus, Lys side chains in binding pockets flex 25 times more often then do the Phe side chains. Normalizing for the number of flexible dihedral bonds in each amino acid attenuates the scale somewhat, however, the clear trend of large, polar amino acids being more flexible in the pocket than aromatic ones remains. We found no correlation between backbone movement of a residue upon ligand binding and the flexibility of its side chain. These results are relevant to 1. Reduction of search space in docking algorithms by inclusion of side-chain flexibility for a limited number of binding pocket residues; and 2. Utilization of the amino acid flexibility scale in protein engineering studies to alter the flexibility of binding pockets. Proteins 2000;39:261-268. {\copyright} 2000 Wiley-Liss, Inc.}, address = {Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel}, author = {Najmanovich, Rafael and Kuttner, Josef and Sobolev, Vladimir and Edelman, Marvin}, citeulike-article-id = {934387}, citeulike-linkout-0 = {http://dx.doi.org/10.1002/(SICI)1097-0134(20000515)39:3%3C261::AID-PROT90%3E3.0.CO;2-4}, citeulike-linkout-1 = {http://www3.interscience.wiley.com/cgi-bin/abstract/71001607/ABSTRACT}, doi = {10.1002/(SICI)1097-0134(20000515)39:3%3C261::AID-PROT90%3E3.0.CO;2-4}, journal = {Proteins: Structure, Function, and Genetics}, keywords = {side\_chain}, number = {3}, pages = {261--268}, posted-at = {2007-06-29 23:54:07}, priority = {4}, title = {Side-chain flexibility in proteins upon ligand binding}, url = {http://dx.doi.org/10.1002/(SICI)1097-0134(20000515)39:3%3C261::AID-PROT90%3E3.0.CO;2-4}, volume = {39}, year = {2000} }

TY - JOUR ID - citeulike:934387 L3 - citeulike-article-id:934387 N2 - Ligand binding may involve a wide range of structural changes in the receptor protein, from hinge movement of entire domains to small side-chain rearrangements in the binding pocket residues. The analysis of side chain flexibility gives insights valuable to improve docking algorithms and can provide an index of amino-acid side-chain flexibility potentially useful in molecular biology and protein engineering studies. In this study we analyzed side-chain rearrangements upon ligand binding. We constructed two non-redundant databases (980 and 353 entries) of ldquopairedrdquo protein structures in complexed (holo-protein) and uncomplexed (apo-protein) forms from the PDB macromolecular structural database. The number and identity of binding pocket residues that undergo side-chain conformational changes were determined. We show that, in general, only a small number of residues in the pocket undergo such changes (e.g., sim85% of cases show changes in three residues or less). The flexibility scale has the following order: Lys > Arg, Gln, Met > Glu, Ile, Leu > Asn, Thr, Val, Tyr, Ser, His, Asp > Cys, Trp, Phe; thus, Lys side chains in binding pockets flex 25 times more often then do the Phe side chains. Normalizing for the number of flexible dihedral bonds in each amino acid attenuates the scale somewhat, however, the clear trend of large, polar amino acids being more flexible in the pocket than aromatic ones remains. We found no correlation between backbone movement of a residue upon ligand binding and the flexibility of its side chain. These results are relevant to 1. Reduction of search space in docking algorithms by inclusion of side-chain flexibility for a limited number of binding pocket residues; and 2. Utilization of the amino acid flexibility scale in protein engineering studies to alter the flexibility of binding pockets. Proteins 2000;39:261-268. © 2000 Wiley-Liss, Inc. IS - 3 JF - Proteins: Structure, Function, and Genetics AD - Plant Sciences Department, Weizmann Institute of Science, Rehovot, Israel EP - 268 TI - Side-chain flexibility in proteins upon ligand binding VL - 39 SP - 261 KW - side_chain AU - Najmanovich, Rafael AU - Kuttner, Josef AU - Sobolev, Vladimir AU - Edelman, Marvin PY - 2000/// UR - http://dx.doi.org/10.1002/(SICI)1097-0134(20000515)39:3%3C261::AID-PROT90%3E3.0.CO;2-4 ER -