Many proteins in their unbound structures have cryptic sites that are not appropriately sized for drug binding. We consider here 32 proteins from the recently published CryptoSite set with validated cryptic sites, and study whether the sites remain cryptic in all available X-ray structures of the proteins solved without any ligand bound near the sites. It was shown that only few of these proteins have binding pockets that never form without ligand binding. Sites that are cryptic in some structures but spontaneously form in others are also rare. In most proteins the forming of pockets is affected by mutations or ligand binding at locations far from the cryptic site. To further explore these mechanisms, we applied adiabatic biased molecular dynamics simulations to guide the proteins from their ligand-free structures to ligand-bound conformations, and studied the distribution of druggability scores of the pockets located at the cryptic sites.

中文翻译：

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基于结构的隐身站点开口分析。

许多蛋白质在其未结合的结构中具有隐蔽位点，其大小不适用于药物结合。在这里，我们考虑来自最近发布的CryptoSite集的32个蛋白质，这些蛋白质具有经过验证的隐含位点，并研究这些位点是否在所解决的蛋白质的所有可用X射线结构中都保持隐秘，并且在位点附近未结合任何配体。结果表明，这些蛋白质中只有极少数具有没有结合配体就不会形成的结合袋。在某些结构中隐秘但在其他结构中自发形成的位点也很少见。在大多数蛋白质中，口袋的形成受远离隐蔽位点的突变或配体结合的影响。为了进一步探索这些机制，我们应用了绝热偏置分子动力学模拟来指导蛋白质从无配体的结构转变为配体结合的构象，