通过增强的采样模拟来了解蛋白中的神秘口袋形成
Vladimiras Oleinikovas, Giorgio Saladino, Benjamin P Cossins1
1UCB Pharma , Slough SL1 3WE, United Kingdom.
Journal of the American Chemical Society
|October 12, 2016
概括
发现蛋白质中的密码口袋是新药开发的关键. 我们的研究表明碎片探测器和新的SWISH方法有效地揭示了这些隐藏的药物目标,克服了模拟挑战.
科学领域:
- 计算化学
- 结构生物学
- 药物发现
背景情况:
- 隐形口袋是药物结合时出现的短暂蛋白质位点,为药物开发提供了新的机会.
- 经典的绑定站点已经得到了很好的研究,但神秘的站点在发现和描述方面存在独特的挑战.
研究的目的:
- 研究药理相关蛋白位中的密码位点的性质和动态.
- 为了比较各种基于模拟的方法的有效性来发现神秘的网站.
- 开发和验证一种新的计算方法来识别可使用的加密口袋.
主要方法:
- 四个药理相关蛋白质的分子动力学 (MD) 模拟.
- 标准MD,增强采样 (并行炼) 和碎片探测技术的评估.
- 开发和应用基于哈密尔顿复制品交换的新方法 (SWISH) 与碎片探测相结合.
- 模拟数据的分析,以了解神秘的站点形成机制,并区分真实口袋和虚假阳性.
主要成果:
- 在未结合的蛋白质的自由能景观中,密码点不存在于稳定的最小值中,并且在模拟中倾向于快速关闭.
- 标准的MD和基于温度的增强采样方法不足以观察神秘部位的开放.
- 在长时间的模拟中,碎片探测偶尔会显示出神秘的部位开放和结合.
- 新的SWISH方法与探测器相结合,对一般神秘地点的发现有显著的前景.
- 提出了一种方法来区分真实可使用药物的神秘口袋和假阳性.
结论:
- 隐秘部位形成涉及诱导适应和形状选择机制之间的相互作用.
- SWISH方法提供了一个强大的计算策略,用于识别神秘的口袋,推动药物发现工作.
- 了解口袋动态对于在药物开发中选择有效的计算方法至关重要.
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