Calculation of protein-ligand binding free energy by using a polarizable potential

@article{citeulike:2735026, abstract = {The binding of charged ligands benzamidine and diazamidine to trypsin was investigated by using a polarizable potential energy function and explicit-water molecular dynamics simulations. The binding free energies were computed from the difference between the free energies of decoupling the ligand from water and protein environments. Both the absolute and the relative free energies from the perturbation simulations agree with experimental measurements to within 0.5 kcal{middle dot}mol-1. Comparison of free-energy components sampled from different thermodynamic paths indicates that electrostatics is the main driving force behind benzamidine recognition of trypsin. The contribution of electronic polarization to binding appears to be crucial. By computing the free-energy contribution caused by the polarization between the ligand and its surroundings, we found that polarization has the opposite effect in dissimilar environments. Although polarization favors ligand solvation in water, it weakens the protein-ligand attraction by screening the electrostatic interaction between trypsin and benzamidine. We also examined the relative binding free energies of a benzamidine analog diazamidine to trypsin. The changes in free energy on benzamidine-diazamidine substitution were tens of kilocalories in both water and trypsin environments; however, the change in the total binding free energy is <2 kcal{middle dot}mol-1 because of cancellation, consistent with the experimental results. Overall, our results suggest that the use of a polarizable force field, given adequate sampling, is capable of achieving chemical accuracy in molecular simulations of protein-ligand recognition. 10.1073/pnas.0711686105}, author = {Jiao, Dian and Golubkov, Pavel A. and Darden, Thomas A. and Ren, Pengyu }, citeulike-article-id = {2735026}, doi = {http://dx.doi.org/10.1073/pnas.0711686105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {toread}, month = {April}, number = {17}, pages = {6290--6295}, posted-at = {2008-04-29 18:41:31}, priority = {2}, title = {Calculation of protein-ligand binding free energy by using a polarizable potential}, url = {http://dx.doi.org/10.1073/pnas.0711686105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2735026 L3 - citeulike-article-id:2735026 TI - Calculation of protein-ligand binding free energy by using a polarizable potential JF - Proceedings of the National Academy of Sciences VL - 105 IS - 17 SP - 6290 EP - 6295 N2 - The binding of charged ligands benzamidine and diazamidine to trypsin was investigated by using a polarizable potential energy function and explicit-water molecular dynamics simulations. The binding free energies were computed from the difference between the free energies of decoupling the ligand from water and protein environments. Both the absolute and the relative free energies from the perturbation simulations agree with experimental measurements to within 0.5 kcal{middle dot}mol-1. Comparison of free-energy components sampled from different thermodynamic paths indicates that electrostatics is the main driving force behind benzamidine recognition of trypsin. The contribution of electronic polarization to binding appears to be crucial. By computing the free-energy contribution caused by the polarization between the ligand and its surroundings, we found that polarization has the opposite effect in dissimilar environments. Although polarization favors ligand solvation in water, it weakens the protein-ligand attraction by screening the electrostatic interaction between trypsin and benzamidine. We also examined the relative binding free energies of a benzamidine analog diazamidine to trypsin. The changes in free energy on benzamidine-diazamidine substitution were tens of kilocalories in both water and trypsin environments; however, the change in the total binding free energy is <2 kcal{middle dot}mol-1 because of cancellation, consistent with the experimental results. Overall, our results suggest that the use of a polarizable force field, given adequate sampling, is capable of achieving chemical accuracy in molecular simulations of protein-ligand recognition. 10.1073/pnas.0711686105 KW - toread AU - Jiao, Dian AU - Golubkov, Pavel AU - Darden, Thomas AU - Ren, Pengyu PY - 2008/04/29/ UR - http://dx.doi.org/10.1073/pnas.0711686105 ER -