Intrinsic Free Energy of the Conformational Transition of the KcsA Signature Peptide from Conducting to Nonconducting State
journal contributionposted on 09.09.2008, 00:00 by Ilja V. Khavrutskii, Mikolai Fajer, J. Andrew McCammon
We explore a conformational transition of the TATTVGYG signature peptide of the KcsA ion selectivity filter and its GYG to AYA mutant from the conducting α-strand state into the nonconducting pII-like state using a novel technique for multidimensional optimization of transition path ensembles and free energy calculations. We find that the wild type peptide, unlike the mutant, intrinsically favors the conducting state due to G77 backbone propensities and additional hydrophobic interaction between the V76 and Y78 side chains in water. The molecular mechanical free energy profiles in explicit water are in very good agreement with the corresponding adiabatic energies from the Generalized Born Molecular Volume (GBMV) implicit solvent model. However comparisons of the energies to higher level B3LYP/6−31G(d) Density Functional Theory calculations with Polarizable Continuum Model (PCM) suggest that the nonconducting state might be more favorable than predicted by molecular mechanics simulations. By extrapolating the single peptide results to the tetrameric channel, we propose a novel hypothesis for the ion selectivity mechanism.
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V 76novel techniqueAYAKcsA Signature PeptideIntrinsic Free Energynonconducting statenovel hypothesisG 77 backbone propensitiesPCMConformational TransitionMolecular Volumetetrameric channellevel B 3LYP Density Functional Theory calculationsTATTVGYG signature peptidePolarizable Continuum ModelY 78 side chainspeptide resultsmechanics simulationsNonconducting StateWetype peptideKcsA ion selectivity filterenergy profilestransition path ensemblesadiabatic energiesGBMVion selectivity mechanismenergy calculations