绝对有约束力的自由能量与OneOPES
Maurice Karrenbrock1,2,3, Alberto Borsatto1,2,3, Valerio Rizzi1,2,3
1School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, CH.
The journal of physical chemistry letters
|September 20, 2024
概括
计算蛋白质 - 配体结合的自由能量是具有挑战性的. 一个新的OneOPES增强采样策略准确地预测了结合 afinities,帮助药物发现和机制研究.
科学领域:
- 计算化学是一种计算化学.
- 分子动力学模拟的模拟.
- 药物发现 药物发现
背景情况:
- 计算蛋白质 - 连接体系统的绝对结合自由能量 (ABFE) 是至关重要的,但历史上具有挑战性.
- 最近在力场和算法方面的进步提高了ABFE计算质量,但药物发现的准确性仍然是一个障碍.
研究的目的:
- 提出一个可转移的增强采样策略,用于精确的ABFE计算蛋白质-连接体系统.
- 用简单的几何集体变量使用OneOPES (单粒子激发采样) 方法验证该策略.
- 评估该策略在与药物发现相关的各种配体和蛋白质标上的表现.
主要方法:
- 使用OneOPES增强采样方法与几何集体变量相结合.
- 将该策略应用于BRD4和Hsp90蛋白点,具有17种不同的配体 (片段和类似药物的分子).
- 将计算的结合自由能量与实验数据进行比较,并评估结合模式和结构一致性的抽样.
主要成果:
- 与实验值相比,在预测蛋白质 - 配体结合亲缘关系方面取得了很高的准确性,平均无标记误差<1 kcal mol−1.
- 证明了该策略在不同的蛋白质标和配体之间无需系统特定的集体变量调的情况下的可转移性.
- 展示了各种连接体结合模式的有效采样和从各种初始配置中实验确定结构的一致复制.
结论:
- 拟议的OneOPES战略提供了一个准确和可转移的方法来计算蛋白质-连接物ABFEs.
- 这种方法可以通过提供可靠的结合亲和力预测,显著地告知药物发现中的优化活动.
- 该策略有助于更深入地了解蛋白质-连接体结合和解结合机制.
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