基于炼金受体跳跃与交换自由能计算的结合选择性分析
Binding Selectivity Analysis from Alchemical Receptor Hopping and Swapping Free Energy Calculations
AI总结：
本文提出基于ATM的受体跳跃和受体交换自由能估计协议，用于模拟配体对两个受体的结合选择性，在主-客体系统和分子片段实验中验证了其准确性与药物发现潜力。
摘要：
我们提出基于炼金转移方法（ATM）的受体跳跃和受体交换自由能估计协议，用于模拟一组配体对两个任意受体的结合选择性。受体跳跃协议在一次模拟中将配体从一个受体炼金转移到另一个受体，直接给出配体对两个受体的结合选择性自由能，即两个独立结合自由能之差。在受体交换协议中，一对配体中的第一个配体从一个受体转移到另一个受体，同时第二个配体沿相反方向转移。受体交换自由能给出一组配体结合选择性自由能的差异，使用广义 DiffNet 算法组合后，得到配体的结合选择性自由能。我们在主-客体系统上测试这些算法，结果表明所得结果与实验数据一致，且与常规方法得到的绝对和相对结合自由能差异相符。对结合胰蛋白酶和凝血酶丝氨酸蛋白酶的分子片段进行选择性分析的初步应用，证实了受体交换技术在基于结构的药物发现中的潜力。本工作提出的新方法是为实现跨具有潜在低序列同一性的蛋白质受体的配体选择性优化的精简且计算高效协议迈出的第一步。
英文摘要：
We present receptor hopping and receptor swapping free energy estimation protocols based on the Alchemical Transfer Method (ATM) to model the binding selectivity of a set of ligands to two arbitrary receptors. The receptor hopping protocol, where a ligand is alchemically transferred from one receptor to another in one simulation, directly yields the ligand's binding selectivity free energy for the two receptors, which is the difference between the two individual binding free energies. In the receptor swapping protocol, the first ligand of a pair is transferred from one receptor to another while the second ligand is simultaneously transferred in the opposite direction. The receptor swapping free energy yields the differences in binding selectivity free energies of a set of ligands, which, when combined using a generalized DiffNet algorithm, yield the binding selectivity free energies of the ligands. We test these algorithms on host-guest systems and show that they yield results that agree with experimental data and are consistent with differences in absolute and relative binding free energies obtained by conventional methods. Preliminary applications to the selectivity analysis of molecular fragments binding to the trypsin and thrombin serine protease confirm the potential of the receptor swapping technology in structure-based drug discovery. The novel methodologies presented in this work are a first step toward streamlined and computationally efficient protocols for ligand selectivity optimization across protein receptors with potentially low sequence identity.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
