Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach. Export

@article{citeulike:3988372, abstract = {A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the binding specificity of acetylcholinesterase (AChE) with its natural substrate acetylcholine (ACh), a family of substrate analogues, and choline. Calculated docking energies are well correlated to experimental k(cat)/K(M) values, as well as to experimental binding affinities of a related series of TMTFA inhibitors. The "esteratic" and "anionic" subsites are found to act together to achieve substrate binding specificity. We find that the presence of ACh in the active site of AChE not only stabilizes the setup of the catalytic triad but also tightens both subsites to achieve better binding. The docking energy gained from this induced fit is 0.7 kcal/mol for ACh. For the binding of the substrate tailgroup to the anionic subsite, both the size and the positive charge of the tailgroup are important. The removal of the positive charge leads to a weaker binding of 1 kcal/mol loss in docking energy. Substituting each tail methyl group with hydrogen results in both an incremental loss in docking energy and also a decrease in the percentage of structures docked in the active site correctly set up for catalysis.}, author = {Kua, J. and Zhang, Y. and McCammon, J. A.}, citeulike-article-id = {3988372}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/12105904}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=12105904}, day = {17}, issn = {0002-7863}, journal = {Journal of the American Chemical Society}, keywords = {docking}, month = {July}, number = {28}, pages = {8260--8267}, posted-at = {2009-01-31 19:19:48}, priority = {2}, title = {Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/12105904}, volume = {124}, year = {2002} }

TY - JOUR ID - citeulike:3988372 L3 - citeulike-article-id:3988372 N2 - A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the binding specificity of acetylcholinesterase (AChE) with its natural substrate acetylcholine (ACh), a family of substrate analogues, and choline. Calculated docking energies are well correlated to experimental k(cat)/K(M) values, as well as to experimental binding affinities of a related series of TMTFA inhibitors. The "esteratic" and "anionic" subsites are found to act together to achieve substrate binding specificity. We find that the presence of ACh in the active site of AChE not only stabilizes the setup of the catalytic triad but also tightens both subsites to achieve better binding. The docking energy gained from this induced fit is 0.7 kcal/mol for ACh. For the binding of the substrate tailgroup to the anionic subsite, both the size and the positive charge of the tailgroup are important. The removal of the positive charge leads to a weaker binding of 1 kcal/mol loss in docking energy. Substituting each tail methyl group with hydrogen results in both an incremental loss in docking energy and also a decrease in the percentage of structures docked in the active site correctly set up for catalysis. IS - 28 JF - Journal of the American Chemical Society SN - 0002-7863 EP - 8267 TI - Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach. VL - 124 SP - 8260 KW - docking AU - Kua, J AU - Zhang, Y AU - McCammon, JA PY - 2002/07/17/ UR - http://view.ncbi.nlm.nih.gov/pubmed/12105904 ER -