Department of Biomedical Sciences, University of Lausanne, 1015 Lausanne, Switzerland.
SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
J Phys Chem B. 2022 Sep 15;126(36):6868-6877. doi: 10.1021/acs.jpcb.2c04593. Epub 2022 Sep 1.
A central problem in computational biophysics is the treatment of titratable residues in molecular dynamics simulations of large biological macromolecular systems. Conventional simulation methods ascribe a fixed ionization state to titratable residues in accordance with their p and the pH of the system, assuming that an effective average model will be able to capture the predominant behavior of the system. While this assumption may be justifiable in many cases, it is certainly limited, and it is important to design alternative methodologies allowing a more realistic treatment. Constant-pH simulation methods provide powerful approaches to handle titratable residues more realistically by allowing the ionization state to vary statistically during the simulation. Extending the molecular mechanical (MM) potential energy function to a family of potential functions accounting for different ionization states, constant-pH simulations are designed to sample all accessible configurations and ionization states, properly weighted according to their Boltzmann factor. Because protonation and deprotonation events correspond to a change in the total charge, difficulties arise when the long-range Coulomb interaction is treated on the basis of an idealized infinite simulation model and periodic boundary conditions with particle-mesh Ewald lattice sums. Charging free-energy calculations performed under these conditions in aqueous solution depend on the Galvani potential of the bulk water phase. This has important implications for the equilibrium and nonequilibrium constant-pH simulation methods grounded in the relative free-energy difference corresponding to the protonated and unprotonated residues. Here, the effect of the Galvani potential is clarified, and a simple practical solution is introduced to address this issue in constant-pH simulations of the acid-sensing ion channel (ASIC).
计算生物物理学中的一个核心问题是在大规模生物大分子系统的分子动力学模拟中处理可滴定残基。传统的模拟方法根据可滴定残基的 p 值和系统的 pH 值为其赋予一个固定的离子化状态，假设有效的平均模型将能够捕捉到系统的主要行为。虽然在许多情况下这种假设可能是合理的，但它肯定是有限的，因此设计替代方法以更真实地处理可滴定残基非常重要。恒 pH 模拟方法通过允许在模拟过程中统计地改变离子化状态，为更真实地处理可滴定残基提供了强大的方法。将分子力学（MM）势能函数扩展到一组考虑不同离子化状态的势能函数，恒 pH 模拟旨在根据其玻尔兹曼因子对所有可访问的构型和离子化状态进行适当加权的统计采样。由于质子化和去质子化事件对应于总电荷的变化，因此当根据理想化的无限模拟模型和具有粒子网格 Ewald 晶格和的周期性边界条件处理长程库仑相互作用时，会出现困难。在这些条件下在水溶液中进行的充电自由能计算取决于本体水相的伽伐尼电势。这对基于质子化和去质子化残基的相对自由能差的平衡和非平衡恒 pH 模拟方法有重要影响。在这里，澄清了伽伐尼电势的影响，并引入了一种简单的实用解决方案来解决在酸感应离子通道（ASIC）的恒 pH 模拟中出现的这个问题。
