Pathway and Endpoint Free Energy Calculations for Cyclic Nucleotide Binding to HCN Channels

@article{citeulike:2954682, abstract = {cAMP and cGMP differentially bind to and regulate a variety of proteins, including cyclic nucleotide-gated (CNG) channels and hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels. Previous site-directed mutagenesis studies have isolated two conserved residues that are critical for enabling certain channels to selectively bind cGMP relative to cAMP. However, no definitive mechanism has been identified that explains the preferential activation of other channels by cAMP. Here we apply computational binding free energy methods, including thermodynamic integration, linear interaction energy, and continuum electrostatic calculations, to gain insights into the mechanisms of cyclic nucleotide selectivity. Consistent with experimental observations, computational results for the cAMP-selective HCN channels show that the binding free energy of cAMP is lower (more favorable) than that of cGMP. Surprisingly, cAMP selectivity is not due to its preferential contacts with protein, but rather reflects the greater hydration energy of cGMP relative to cAMP, resulting in a greater energetic cost for cGMP binding. 10.1529/biophysj.108.130872}, author = {Zhou, Lei and Siegelbaum, Steven A. }, citeulike-article-id = {2954682}, doi = {http://dx.doi.org/10.1529/biophysj.108.130872}, journal = {Biophys. J.}, keywords = {binding, electrostatics, free\_energy, md\_simulation, protein-ligand}, month = {June}, number = {12}, pages = {L90--92}, posted-at = {2008-07-08 00:49:17}, priority = {2}, title = {Pathway and Endpoint Free Energy Calculations for Cyclic Nucleotide Binding to HCN Channels}, url = {http://dx.doi.org/10.1529/biophysj.108.130872}, volume = {94}, year = {2008} }

TY - JOUR ID - citeulike:2954682 L3 - citeulike-article-id:2954682 TI - Pathway and Endpoint Free Energy Calculations for Cyclic Nucleotide Binding to HCN Channels JF - Biophys. J. VL - 94 IS - 12 SP - L90 EP - 92 N2 - cAMP and cGMP differentially bind to and regulate a variety of proteins, including cyclic nucleotide-gated (CNG) channels and hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels. Previous site-directed mutagenesis studies have isolated two conserved residues that are critical for enabling certain channels to selectively bind cGMP relative to cAMP. However, no definitive mechanism has been identified that explains the preferential activation of other channels by cAMP. Here we apply computational binding free energy methods, including thermodynamic integration, linear interaction energy, and continuum electrostatic calculations, to gain insights into the mechanisms of cyclic nucleotide selectivity. Consistent with experimental observations, computational results for the cAMP-selective HCN channels show that the binding free energy of cAMP is lower (more favorable) than that of cGMP. Surprisingly, cAMP selectivity is not due to its preferential contacts with protein, but rather reflects the greater hydration energy of cGMP relative to cAMP, resulting in a greater energetic cost for cGMP binding. 10.1529/biophysj.108.130872 KW - binding KW - electrostatics KW - free_energy KW - md_simulation KW - protein-ligand AU - Zhou, Lei AU - Siegelbaum, Steven PY - 2008/06/15/ UR - http://dx.doi.org/10.1529/biophysj.108.130872 ER -