PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations.,Journal of Chemical Information and Modeling

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PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-03-16 , DOI: 10.1021/acs.jcim.9b01209
Gerard Martinez-Rosell ₁ , Silvia Lovera ₂ , Zara A Sands ₂ , Gianni De Fabritiis _{1,

3,

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Affiliation

Cryptic pockets are protein cavities that remain hidden in resolved apo structures and generally require the presence of a co-crystallized ligand to become visible. Finding new cryptic pockets is crucial for structure-based drug discovery to identify new ways of modulating protein activity and thus expand the druggable space. We present here a new method and associated web application leveraging mixed-solvent molecular dynamics (MD) simulations using benzene as a hydrophobic probe to detect cryptic pockets. Our all-atom MD-based workflow was systematically tested on 18 different systems and 5 additional kinases and represents the largest validation study of this kind. CrypticScout identifies benzene probe binding hotspots on a protein surface by mapping probe occupancy, residence time, and the benzene occupancy reweighed by the residence time. The method is presented to the scientific community in a web application available via www.playmolecule.org using a distributed computing infrastructure to perform the simulations.

中文翻译：

PlayMolecule CrypticScout：使用混合溶剂分子模拟预测蛋白质的密码学位点。

隐窝是保留在解析的载脂蛋白结构中的蛋白质空腔，通常需要共结晶配体的存在才能变得可见。寻找新的隐秘口袋对于基于结构的药物发现至关重要，以发现调节蛋白质活性并从而扩大可药物利用空间的新方法。我们在这里介绍一种新方法和相关的Web应用程序，利用苯作为疏水探针的混合溶剂分子动力学（MD）模拟，以检测隐秘口袋。我们基于全原子MD的工作流程已在18种不同系统和5种其他激酶上进行了系统测试，代表了此类研究中规模最大的验证。CrypticScout通过映射探针占用率，停留时间以及通过停留时间重新称重的苯占用率来识别蛋白质表面上的苯探针结合热点。

更新日期：2020-03-16

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