Khavrutskii Ilja V, Fajer Mikolai, McCammon J Andrew
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093-0365.
J Chem Theory Comput. 2008 Sep 9;4(9):1541-1554. doi: 10.1021/ct800086s.
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.
我们使用一种用于过渡路径系综多维优化和自由能计算的新技术，探索了KcsA离子选择性过滤器的TATTVGYG特征肽及其从导电α-链状态到非导电pII样状态的GYG到AYA突变体的构象转变。我们发现，与突变体不同，野生型肽由于G77主链倾向以及水中V76和Y78侧链之间额外的疏水相互作用，本质上更倾向于导电状态。在显式水中的分子力学自由能分布与广义玻恩分子体积（GBMV）隐式溶剂模型的相应绝热能量非常吻合。然而，将这些能量与使用极化连续介质模型（PCM）的更高水平B3LYP/6-31G(d)密度泛函理论计算进行比较表明，非导电状态可能比分子力学模拟预测的更有利。通过将单个肽的结果外推到四聚体通道，我们提出了一种关于离子选择性机制的新假设。
