磷脂酶 C 的标准结合自由能和膜解吸机制,Journal of Chemical Information and Modeling

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磷脂酶 C 的标准结合自由能和膜解吸机制
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-03-28 , DOI: 10.1021/acs.jcim.1c01543
Emmanuel E Moutoussamy _{1,

2} , Hanif M Khan _{1,

2} , Mary F Roberts ₃ , Anne Gershenson ₄ , Christophe Chipot _{5,

6} , Nathalie Reuter _{2,

7}

Affiliation

外周膜蛋白 (PMP) 暂时结合到细胞膜上，并在信号转导、脂质代谢和膜运输中发挥重要作用。使用实验技术获得准确的膜-PMP 亲和力比在水溶液中获得蛋白质-配体亲和力更具挑战性。在理论层面上，由于生物体的大小、缓慢的脂质扩散以及伴随结合的构型熵的巨大变化，使用分子动力学模拟计算标准蛋白质-膜结合自由能仍然是一项艰巨的挑战过程。为了克服这些挑战，我们使用了一个计算框架，该框架依赖于一系列平均力势 (PMF) 计算，包括一组对集体变量的几何约束。选择苏云金芽孢杆菌磷脂酰肌醇特异性磷脂酶 C ( Bt PI-PLC) 是因为其作为毒力因子的重要性以及大量可用的实验亲和数据。我们计算出的标准结合自由能为 -8.2 ± 1.4 kcal/mol，与报告的实验值（-6.6 ± 0.2 kcal/mol）合理一致。根据 2.3 μs 分离 PMF 计算，我们研究了Bt PI-PLC 在分离过程中脱离与脂质双层相互作用的机制。我们描述了一个短的两亲性螺旋如何参与短暂的相互作用，以缓解其疏水物在从双层解吸时通过界面区域的通道。

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Standard Binding Free Energy and Membrane Desorption Mechanism for a Phospholipase C

Peripheral membrane proteins (PMPs) bind temporarily to cellular membranes and play important roles in signaling, lipid metabolism, and membrane trafficking. Obtaining accurate membrane-PMP affinities using experimental techniques is more challenging than for protein–ligand affinities in an aqueous solution. At the theoretical level, calculation of the standard protein–membrane binding free energy using molecular dynamics simulations remains a daunting challenge owing to the size of the biological objects at play, the slow lipid diffusion, and the large variation in configurational entropy that accompanies the binding process. To overcome these challenges, we used a computational framework relying on a series of potential-of-mean-force (PMF) calculations including a set of geometrical restraints on collective variables. This methodology allowed us to determine the standard binding free energy of a PMP to a phospholipid bilayer using an all-atom force field. Bacillus thuringiensis phosphatidylinositol-specific phospholipase C (BtPI-PLC) was chosen due to its importance as a virulence factor and owing to the host of experimental affinity data available. We computed a standard binding free energy of −8.2 ± 1.4 kcal/mol in reasonable agreement with the reported experimental values (−6.6 ± 0.2 kcal/mol). In light of the 2.3-μs separation PMF calculation, we investigated the mechanism whereby BtPI-PLC disengages from interactions with the lipid bilayer during separation. We describe how a short amphipathic helix engages in transitory interactions to ease the passage of its hydrophobes through the interfacial region upon desorption from the bilayer.

更新日期：2022-03-28

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