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配体高斯加速分子动力学3(LiGaMD3):小分子和柔性肽结合热力学与动力学的改进计算

Ligand Gaussian accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides.

作者信息

Wang Jinan, Miao Yinglong

机构信息

Computational Medicine Program and Department of Pharmacology, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, USA 27599.

出版信息

bioRxiv. 2024 May 8:2024.05.06.592668. doi: 10.1101/2024.05.06.592668.

Abstract

Binding thermodynamics and kinetics play critical roles in drug design. However, it has proven challenging to efficiently predict ligand binding thermodynamics and kinetics of small molecules and flexible peptides using conventional Molecular Dynamics (cMD), due to limited simulation timescales. Based on our previously developed Ligand Gaussian accelerated Molecular Dynamics (LiGaMD) method, we present a new approach, termed "LiGaMD3", in which we introduce triple boosts into three individual energy terms that play important roles in small-molecule/peptide dissociation, rebinding and system conformational changes to improve the sampling efficiency of small-molecule/peptide interactions with target proteins. To validate the performance of LiGaMD3, MDM2 bound by a small molecule (Nutlin 3) and two highly flexible peptides (PMI and P53) were chosen as model systems. LiGaMD3 could efficiently capture repetitive small-molecule/peptide dissociation and binding events within 2 microsecond simulations. The predicted binding kinetic constant rates and free energies from LiGaMD3 agreed with available experimental values and previous simulation results. Therefore, LiGaMD3 provides a more general and efficient approach to capture dissociation and binding of both small-molecule ligand and flexible peptides, allowing for accurate prediction of their binding thermodynamics and kinetics.

摘要

结合热力学和动力学在药物设计中起着关键作用。然而,由于模拟时间尺度有限,使用传统分子动力学(cMD)有效预测小分子和柔性肽的配体结合热力学和动力学已被证明具有挑战性。基于我们之前开发的配体高斯加速分子动力学(LiGaMD)方法,我们提出了一种新方法,称为“LiGaMD3”,其中我们在小分子/肽解离、重新结合和系统构象变化中起重要作用的三个单独能量项中引入三重增强,以提高小分子/肽与靶蛋白相互作用的采样效率。为了验证LiGaMD3的性能,选择了由小分子(Nutlin 3)和两种高度柔性肽(PMI和P53)结合的MDM2作为模型系统。LiGaMD3可以在2微秒的模拟中有效捕获重复的小分子/肽解离和结合事件。LiGaMD3预测的结合动力学常数速率和自由能与现有实验值和先前的模拟结果一致。因此,LiGaMD3提供了一种更通用、更有效的方法来捕获小分子配体和柔性肽的解离和结合,从而能够准确预测它们的结合热力学和动力学。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8091/11100592/2e8365d1ada8/nihpp-2024.05.06.592668v1-f0002.jpg

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