Protein–protein interactions (PPIs) are essential for the function of many proteins. Aberrant PPIs have the potential to lead to disease, making PPIs promising targets for drug discovery. There are over 64,000 PPIs in the human interactome reference database; however, to date, very few PPI modulators have been approved for clinical use. Further development of PPI-specific therapeutics is highly dependent on the availability of structural data and the existence of reliable computational tools to explore the interface between two interacting proteins. The fragment molecular orbital (FMO) quantum mechanics method offers comprehensive and computationally inexpensive means of identifying the strength (in kcal/mol) and the chemical nature (electrostatic or hydrophobic) of the molecular interactions taking place at the protein–protein interface. We have integrated FMO and PPI exploration (FMO-PPI) to identify the residues that are critical for protein–protein binding (hotspots). To validate this approach, we have applied FMO-PPI to a dataset of protein–protein complexes representing several different protein subfamilies and obtained FMO-PPI results that are in agreement with published mutagenesis data. We observed that critical PPIs can be divided into three major categories: interactions between residues of two proteins (intermolecular), interactions between residues within the same protein (intramolecular), and interactions between residues of two proteins that are mediated by water molecules (water bridges). We extended our findings by demonstrating how this information obtained by FMO-PPI can be utilized to support the structure-based drug design of PPI modulators (SBDD-PPI).

中文翻译：

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使用片段分子轨道法的蛋白质-蛋白质相互作用调节剂的热点识别和药物设计

蛋白质-蛋白质相互作用 (PPI) 对于许多蛋白质的功能至关重要。异常的 PPI 有可能导致疾病，使 PPI 成为药物发现的有希望的目标。人类交互组参考数据库中有超过 64,000 个 PPI；然而，迄今为止，很少有 PPI 调节剂被批准用于临床。PPI 特异性疗法的进一步发展高度依赖于结构数据的可用性和可靠的计算工具的存在，以探索两种相互作用的蛋白质之间的界面。片段分子轨道 (FMO) 量子力学方法提供了全面且计算成本低廉的方法来确定蛋白质-蛋白质界面处发生的分子相互作用的强度（以 kcal/mol 为单位）和化学性质（静电或疏水性）。我们整合了 FMO 和 PPI 探索 (FMO-PPI) 来识别对蛋白质-蛋白质结合（热点）至关重要的残基。为了验证这种方法，我们将 FMO-PPI 应用于代表几个不同蛋白质亚家族的蛋白质-蛋白质复合物数据集，并获得了与已发表的诱变数据一致的 FMO-PPI 结果。我们观察到关键的 PPI 可以分为三大类：两种蛋白质残基之间的相互作用（分子间）、同一蛋白质内残基之间的相互作用（分子内）以及由水分子介导的两种蛋白质残基之间的相互作用（水桥）。 ）。我们通过展示如何利用 FMO-PPI 获得的这些信息来支持基于结构的 PPI 调节剂药物设计 (SBDD-PPI) 来扩展我们的研究结果。