Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Hyogo, Japan.
Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Osaka, Japan.
Molecules. 2022 Sep 5;27(17):5726. doi: 10.3390/molecules27175726.
Proper balance between protein-protein and protein-water interactions is vital for atomistic molecular dynamics (MD) simulations of globular proteins as well as intrinsically disordered proteins (IDPs). The overestimation of protein-protein interactions tends to make IDPs more compact than those in experiments. Likewise, multiple proteins in crowded solutions are aggregated with each other too strongly. To optimize the balance, Lennard-Jones (LJ) interactions between protein and water are often increased about 10% (with a scaling parameter, λ = 1.1) from the existing force fields. Here, we explore the optimal scaling parameter of protein-water LJ interactions for CHARMM36m in conjunction with the modified TIP3P water model, by performing enhanced sampling MD simulations of several peptides in dilute solutions and conventional MD simulations of globular proteins in dilute and crowded solutions. In our simulations, 10% increase of protein-water LJ interaction for the CHARMM36m cannot maintain stability of a small helical peptide, (AAQAA) in a dilute solution and only a small modification of protein-water LJ interaction up to the 3% increase (λ = 1.03) is allowed. The modified protein-water interactions are applicable to other peptides and globular proteins in dilute solutions without changing thermodynamic properties from the original CHARMM36m. However, it has a great impact on the diffusive properties of proteins in crowded solutions, avoiding the formation of too sticky protein-protein interactions.
蛋白质-蛋白质和蛋白质-水相互作用的适当平衡对于球状蛋白质以及天然无序蛋白质 (IDP) 的原子分子动力学 (MD) 模拟至关重要。蛋白质-蛋白质相互作用的高估往往会使 IDP 比实验中的更紧凑。同样，拥挤溶液中的多个蛋白质也会彼此强烈聚集。为了优化平衡，通常将蛋白质-水 Lennard-Jones (LJ) 相互作用从现有力场增加约 10%（使用缩放参数 λ=1.1）。在这里，我们通过在稀溶液中进行几种肽的增强采样 MD 模拟以及在稀溶液和拥挤溶液中进行球状蛋白质的常规 MD 模拟，探索了 CHARMM36m 中蛋白质-水 LJ 相互作用的最佳缩放参数与改进的 TIP3P 水模型结合使用。在我们的模拟中，CHARMM36m 中蛋白质-水 LJ 相互作用增加 10% 无法维持稀溶液中小螺旋肽 (AAQAA) 的稳定性，只允许将蛋白质-水 LJ 相互作用进行小的修改，增加幅度为 3%（λ=1.03）。修改后的蛋白质-水相互作用适用于稀溶液中的其他肽和球状蛋白质，而不会从原始 CHARMM36m 改变热力学性质。然而，它对拥挤溶液中蛋白质的扩散性质有很大影响，避免了形成过于粘性的蛋白质-蛋白质相互作用。
