In the context of advanced hit-to-lead drug design based on atomistic molecular dynamics simulations, we propose a dual topology alchemical approach for calculating the relative binding free energy (RBFE) between two chemically distant compounds. The method (termed NE-RBFE) relies on the enhanced sampling of the end-states in bulk and in the bound state via Hamiltonian Replica Exchange, alchemically connected by a series of independent and fast nonequilibrium (NE) simulations. The technique has been implemented in a bidirectional fashion, applying the Crooks theorem to the NE work distributions for RBFE predictions. The dissipation of the NE process, negatively affecting accuracy, has been minimized by introducing a smooth regularization based on shifted electrostatic and Lennard-Jones non bonded potentials. As a challenging testbed, we have applied our method to the calculation of the RBFEs in the recent host–guest SAMPL international contest, featuring a macrocyclic host with guests varying in the net charge, volume, and chemical fingerprints. Closure validation has been successfully verified in cycles involving compounds with disparate Tanimoto coefficients, volume, and net charge. NE-RBFE is specifically tailored for massively parallel facilities and can be used with little or no code modification on most of the popular software packages supporting nonequilibrium alchemical simulations, such as Gromacs, Amber, NAMD, or OpenMM. The proposed methodology bypasses most of the entanglements and limitations of the standard single topology RBFE approach for strictly congeneric series based on free-energy perturbation, such as slowly relaxing cavity water, sampling issues along the alchemical stratification, and the need for highly overlapping molecular fingerprints.

中文翻译：

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使用双向非平衡方法计算化学距离较远的化合物之间的相对结合自由能


在基于原子分子动力学模拟的先进先导药物设计的背景下，我们提出了一种双拓扑炼金方法，用于计算两种化学距离较远的化合物之间的相对结合自由能（RBFE）。该方法（称为 NE-RBFE）依赖于通过哈密顿副本交换对最终状态进行批量和束缚态的增强采样，并通过一系列独立且快速的非平衡 (NE) 模拟进行炼金术连接。该技术以双向方式实现，将克鲁克斯定理应用于 RBFE 预测的 NE 工作分布。通过引入基于移动静电和 Lennard-Jones 非键合电势的平滑正则化，可以最大限度地减少 NE 过程的耗散，从而对精度产生负面影响。作为一个具有挑战性的测试平台，我们在最近的主客体 SAMPL 国际竞赛中应用了我们的方法来计算 RBFE，该竞赛以大环主体和净电荷、体积和化学指纹各不相同的客体为特色。封闭验证已在涉及具有不同谷本系数、体积和净电荷的化合物的循环中成功得到验证。 NE-RBFE 专为大规模并行设施量身定制，无需修改代码即可在大多数支持非平衡炼金模拟的流行软件包（例如 Gromacs、Amber、NAMD 或 OpenMM）上使用。所提出的方法绕过了标准单拓扑 RBFE 方法的大部分纠缠和限制，适用于基于自由能扰动的严格同属系列，例如缓慢松弛的空腔水、沿炼金分层的采样问题以及高度重叠的分子指纹的需要。