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10.1021/acs.jctc.6b00532 http://scihub22266oqcxt.onion/10.1021/acs.jctc.6b00532 C5021633!5021633!27462935     free     free     free Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Chem+Theory+Comput 2016 ; 12 (9): 4620-31 Nephropedia Template TP {{tp|p=27462935|t=2016. Sensitivity in binding free energies due to protein reorganization |pdf=|usr=}}{{27462935}} gab.com Text Sensitivity in binding free energies due to protein reorganization JO: J Chem Theory Comput http://www.kidney.de/pget.php?&tw=1&pmid=27462935 #FOAvip Tremendous recent improvements in computer hardware, coupled with advances in sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used to aid pharmaceutical drug discovery projects. However, despite these recent innovations, there are still needs for further improvement in sampling algorithms to more adequately sample protein motion relevant to protein-ligand binding. Here, we report our work identifying and studying such clear and remaining needs in the apolar cavity of T4 Lysozyme L99A. In this study, we model recent experimental results that show the progressive opening of the binding pocket in response to a series of homologous ligands.1 Even while using enhanced sampling techniques, we demonstrate that the predicted relative binding free energies (RBFE) are sensitive to the initial protein conformational state. Particularly, we highlight the importance of sufficient sampling of protein conformational changes and demonstrate how inclusion of three key protein residues in the ?hot? region of the FEP/REST simulation improves the sampling and resolves this sensitivity. Twit Text FOAVip Sensitivity in binding free energies due to protein reorganization ????J Chem Theory Comput http://www.kidney.de/pget.php?&tw=1&pmid=27462935 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27462935 #FOAvip English Wikipedia <ref>{{Cite pmid|27462935}}</ref> Sensitivity in binding free energies due to protein reorganization #MMPMID27462935 Lim NM; Wang L; Abel R; Mobley DL J Chem Theory Comput 2016[Sep]; 12 (9): 4620-31 PMID27462935show ga Tremendous recent improvements in computer hardware, coupled with advances in sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used to aid pharmaceutical drug discovery projects. However, despite these recent innovations, there are still needs for further improvement in sampling algorithms to more adequately sample protein motion relevant to protein-ligand binding. Here, we report our work identifying and studying such clear and remaining needs in the apolar cavity of T4 Lysozyme L99A. In this study, we model recent experimental results that show the progressive opening of the binding pocket in response to a series of homologous ligands.1 Even while using enhanced sampling techniques, we demonstrate that the predicted relative binding free energies (RBFE) are sensitive to the initial protein conformational state. Particularly, we highlight the importance of sufficient sampling of protein conformational changes and demonstrate how inclusion of three key protein residues in the ?hot? region of the FEP/REST simulation improves the sampling and resolves this sensitivity. äSensitivity in binding free energies due to protein reorganization (epmc).pdf DeepDyve Pubget Overpricing