Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
J Chem Phys. 2011 Feb 7;134(5):054114. doi: 10.1063/1.3519057.
The accurate prediction of absolute protein-ligand binding free energies is one of the grand challenge problems of computational science. Binding free energy measures the strength of binding between a ligand and a protein, and an algorithm that would allow its accurate prediction would be a powerful tool for rational drug design. Here we present the development of a new method that allows for the absolute binding free energy of a protein-ligand complex to be calculated from first principles, using a single simulation. Our method involves the use of a novel reaction coordinate that swaps a ligand bound to a protein with an equivalent volume of bulk water. This water-swap reaction coordinate is built using an identity constraint, which identifies a cluster of water molecules from bulk water that occupies the same volume as the ligand in the protein active site. A dual topology algorithm is then used to swap the ligand from the active site with the identified water cluster from bulk water. The free energy is then calculated using replica exchange thermodynamic integration. This returns the free energy change of simultaneously transferring the ligand to bulk water, as an equivalent volume of bulk water is transferred back to the protein active site. This, directly, is the absolute binding free energy. It should be noted that while this reaction coordinate models the binding process directly, an accurate force field and sufficient sampling are still required to allow for the binding free energy to be predicted correctly. In this paper we present the details and development of this method, and demonstrate how the potential of mean force along the water-swap coordinate can be improved by calibrating the soft-core Coulomb and Lennard-Jones parameters used for the dual topology calculation. The optimal parameters were applied to calculations of protein-ligand binding free energies of a neuraminidase inhibitor (oseltamivir), with these results compared to experiment. These results demonstrate that the water-swap coordinate provides a viable and potentially powerful new route for the prediction of protein-ligand binding free energies.
准确预测蛋白质-配体的绝对结合自由能是计算科学的重大挑战之一。结合自由能衡量配体与蛋白质之间的结合强度，如果有一种算法能够准确预测结合自由能，它将成为合理药物设计的有力工具。在这里，我们提出了一种新方法的发展，该方法允许从第一性原理计算蛋白质-配体复合物的绝对结合自由能，仅使用单个模拟。我们的方法涉及使用一种新的反应坐标，该坐标通过交换与蛋白质结合的配体与等效体积的本体水来交换配体。该水交换反应坐标使用恒等约束来构建，该约束从本体水中识别占据蛋白质活性部位中配体相同体积的水分子簇。然后使用双重拓扑算法将配体从活性部位与从本体水中识别的水分子簇交换。然后使用复制交换热力学积分来计算自由能。这返回了同时将配体转移到本体水中的自由能变化，因为相同体积的本体水被转移回蛋白质活性部位。这直接是绝对结合自由能。需要注意的是，虽然该反应坐标直接模拟了结合过程，但仍需要准确的力场和足够的采样，以正确预测结合自由能。在本文中，我们介绍了该方法的细节和发展，并展示了如何通过校准用于双重拓扑计算的软核库仑和 Lennard-Jones 参数来提高水交换坐标沿的平均力势能。将最佳参数应用于神经氨酸酶抑制剂（奥司他韦）的蛋白质-配体结合自由能计算，并将这些结果与实验进行比较。这些结果表明，水交换坐标为预测蛋白质-配体结合自由能提供了一种可行且潜在强大的新途径。
