An Integrative Framework for Mapping Orientational Landscapes of Peripheral Membrane Proteins by Paramagnetic NMR and Atomistic Simulation.

IF 8.5 Q1 CHEMISTRY, MULTIDISCIPLINARY
JACS Au Pub Date : 2025-06-05 eCollection Date: 2025-06-23 DOI:10.1021/jacsau.5c00331
Dan Liu, Yu Ni, Leilei Shui, Dong Long
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引用次数: 0

Abstract

The functions of peripheral membrane proteins (PMPs) can be critically influenced by their orientations on membrane surfaces, which are inherently dynamic and challenging to characterize with precision. Molecular dynamics (MD) simulations, while powerful, face limitations in force field accuracy and sampling, particularly for systems involving intricate protein-lipid interactions. Here, we employ artifact-free membrane paramagnetic relaxation enhancement (mPRE) data as a quantitative benchmark to evaluate and refine MD simulations of KRas4B, a classical PMP, bound to anionic bilayers. Discrepancies between state-of-the-art simulations and experimental data are quantified and attributed to both inadequate sampling and force field inaccuracies. By fine-tuning the electrostatic interactions between the negatively charged protein and lipid, moderate improvement in agreement with experimental data was achieved. Furthermore, we employed the maximum entropy method (MEM) to reconcile MD simulations with the mPRE rates, generating a statistically robust orientational ensemble that quantitatively reproduces the mPRE measurements. This integrative approach establishes a powerful framework for atomic-detail characterization of orientational landscapes of PMPs, offering insights into their functional regulation and guiding therapeutic strategies.

用顺磁核磁共振和原子模拟绘制外周膜蛋白取向景观的综合框架。
外周膜蛋白(pmp)的功能可能受到其在膜表面的取向的严重影响,其本质上是动态的,难以精确表征。分子动力学(MD)模拟虽然功能强大,但在力场精度和采样方面存在局限性,特别是对于涉及复杂的蛋白质-脂质相互作用的系统。在这里,我们采用无伪影膜顺磁松弛增强(mPRE)数据作为定量基准来评估和完善KRas4B的MD模拟,KRas4B是一种经典的PMP,结合在阴离子双层上。最先进的模拟和实验数据之间的差异被量化,并归因于采样不足和力场不准确。通过微调带负电荷的蛋白质与脂质之间的静电相互作用,实现了与实验数据一致的适度改善。此外,我们采用最大熵法(MEM)来调和MD模拟与mPRE速率,生成一个统计上稳健的方向集合,定量地再现了mPRE的测量结果。这种综合方法为pmp定向景观的原子细节特征建立了一个强大的框架,为其功能调节和指导治疗策略提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.10
自引率
0.00%
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审稿时长
10 weeks
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