Pathway and endpoint free energy calculations for cyclic nucleotide binding to HCN channels.

Biophysical Journal
Lei Zhou, S A Siegelbaum

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.

References

Nov 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·W AltenhofenU B Kaupp
May 26, 1995·Science·B Honig, A Nicholls
Aug 23, 2001·Proceedings of the National Academy of Sciences of the United States of America·N A BakerJ A McCammon
Jun 15, 2007·Structure·Galen E FlynnWilliam N Zagotta

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Citations

Sep 11, 2010·The Journal of Biological Chemistry·Xinping XuLei Zhou
Jul 2, 2014·The Journal of General Physiology·João PessoaJoão H Morais-Cabral
Jun 25, 2014·Proceedings of the National Academy of Sciences of the United States of America·Michael C PuljungStefan Stoll
Jul 9, 2009·Physiological Reviews·Martin BielXiangang Zong
Mar 13, 2014·ACS Chemical Biology·Stefan MöllerFriedrich W Herberg

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