Membrane environment modulates the pKa values of transmembrane helices.

In this work, we apply the recently developed constant pH molecular dynamics technique to study protonation equilibria of titratable side chains in the context of simple transmembrane (TM) helices and explore the effect of pH on their configurations in membrane bilayers. We observe that, despite a significant shift toward neutral states, considerable population of different side chains stay in the charged state that give rise to pKa values around 9.6 for Asp and Glu and 4.5 to 6 for His and Lys side chains, respectively. These charged states are highly stabilized by favorable interactions between head groups, water molecules, and the charged side chains that are facilitated by substantial changes in the configuration of the peptides. The pH dependent configurations and the measured pKa values are in good agreement with relatively recent solid state NMR measurements. Our results presented here demonstrate that all-atom constant pH molecular dynamics can be applied to membrane proteins and peptides to obtain reliable pKa values and pH dependent behavior for these systems.

在这项工作中，我们应用最近开发的恒pH分子动力学技术来研究在简单跨膜（TM）螺旋环境中可滴定侧链的质子化平衡，并探究pH对它们在膜双层中构象的影响。我们观察到，尽管向中性状态有显著偏移，但相当数量的不同侧链仍处于带电状态，这使得天冬氨酸（Asp）和谷氨酸（Glu）的pKa值约为9.6，组氨酸（His）和赖氨酸（Lys）侧链的pKa值分别为4.5到6。这些带电状态通过头部基团、水分子和带电侧链之间的有利相互作用而高度稳定，肽的构象发生显著变化促进了这种相互作用。pH依赖的构象和测得的pKa值与相对较新的固态核磁共振测量结果非常吻合。我们在此展示的结果表明，全原子恒pH分子动力学可应用于膜蛋白和肽，以获得这些系统可靠的pKa值和pH依赖行为。