Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

中文翻译：

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蛋白质-配体的界面是两极分化的：发现分子间氢键的强烈趋势有利于蛋白质方面的供体，对预测和设计配体复合物具有重要意义。

理解蛋白质如何编码配体特异性非常有趣，并且其重要性与解密遗传密码相似。对于蛋白质-配体识别，几乎无限多种界面形状和化学基团模式组合在一起使该问题特别具有挑战性。在这里，我们分析了具有小生物配体的非同源蛋白质中的数据，以解决我们在抑制剂发现项目中所做的观察：蛋白质倾向于将H键提供给配体，并避免同时使用具有H键供体和受体能力的基团。产生的清晰显着的化学基团匹配偏好阐明了蛋白质天然配体结合的代码，类似于在核酸碱基配对中发现的显性模式。一般，生物配体中出现的90％的酮基和羧酸基氧直接与蛋白质形成H键。发现蛋白质原子起氢键供体和配体原子起受体的作用有两个方面，所有分子间氢键中有76％涉及胺供体。在一起，与令人满意的供体基团相关的严格的化学和几何约束产生了氢键锁，该氢键锁只能由带有正确的富受体键的配体匹配。基于观察到的化学趋势测量H键优先指数已证明足以预测其他蛋白质-配体复合物，并可用于指导分子设计。