Accurate Calculation of Relative Binding Free Energies between Ligands with Different Net Charges
Accurate Calculation of Relative Binding Free Energies between Ligands with Different Net Charges
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DOI：
10.1021/acs.jctc.8b00825
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发表时间：
2018-12-01
影响因子：
5.5
通讯作者：
Wang, Lingle
中科院分区：
文献类型：
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作者：
Chen, Wei;Deng, Yuqing;Wang, Lingle
在药物发现计划中，通常认为改变配体净电荷的修改通常被认为是为了提高约束力和溶解度，或解决其他ADME/TOX问题。准确计算与电荷改变扰动相关的结合自由能变化仍然是计算药物发现中核心重要性的巨大挑战。与普通分子动力学中采用的周期性边界条件和晶格求和相关的有限尺寸效应在静电势能计算中引入了伪影，需要仔细处理，以在具有不同净电荷的系统之间进行准确的自由能计算。实验结合亲和力测定的缓冲溶液中的盐也对带电物种之间的结合自由能具有很强的影响，这进一步使电荷变化扰动的建模变得复杂。在这里，我们扩展了自由能扰动（FEP）算法，该算法已广泛地应用于许多具有相同净电荷（保存电荷摄动）的配体之间相对结合的自由能计算的药物发现程序，以启用收费的费用变化，以改变费用的费用，以改变费用。 。我们已经研究了三种不同的方法来纠正有限尺寸效应，并在10个蛋白质靶标和31次电荷变化的扰动上测试了它们。我们发现，所有三种方法都能够成功消除与蛮力FEP相关的计算结合自由能的盒子尺寸依赖性。此外，包含与实验缓冲溶液的离子强度相匹配的盐可以显着改善计算出的结合自由能。对于具有多种可能质子化态的配体，我们应用了PK（a）校正来考虑配体的电离平衡，结果得到显着改善。最后，这些方法中计算出的结合自由能相互一致，并且与实验结果吻合。计算出的结合自由能和实验数据之间的根平方误差为1.1 kcal/mol，与电荷持有扰动的准确性相当。我们预计，在广泛的目标类别中，此处证明的出色准确性可能会对药物发现项目产生重大影响，在这些项目中必须考虑改变收费的修改。
In drug discovery programs, modifications that change the net charge of the ligands are often considered to improve the binding potency and solubility, or to address other ADME/Tox problems. Accurate calculation of the binding free energy changes associated with charge-changing perturbations remains a great challenge of central importance in computational drug discovery. The finite size effects associated with periodic boundary condition and lattice summation employed in common molecular dynamics simulations introduce artifacts in the electrostatic potential energy calculations, which need to be carefully handled for accurate free-energy calculations between systems with different net charges. The salts in the buffer solution of experimental binding affinity assays also have a strong effect on the binding free energies between charged species, which further complicates the modeling of the charge changing perturbations. Here, we extend our free-energy perturbation (FEP) algorithm, which has been extensively applied to many drug discovery programs for relative binding free-energy calculations between ligands with the same net charge (charge conserving perturbation), to enable charge-changing perturbations. We have investigated three different approaches to correct the finite size effects and tested them on 10 protein targets and 31 charge-changing perturbations. We have found that all three methods are able to successfully eliminate the box-size dependence of calculated binding free energies associated with brute force FEP. Moreover, inclusion of salts matching the ionic strength of experimental buffer solution significantly improves the calculated binding free energies. For ligands with multiple possible protonation states, we applied the pK(a) correction to account for the ionization equilibrium of the ligands and the results are significantly improved. Finally, the calculated binding free energies from these methods agree with each other, and also agree well with the experimental results. The root-mean-square error between the calculated binding free energies and experimental data is 1.1 kcal/mol, which is on par with the accuracy of charge-conserving perturbations. We anticipate that the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for drug discovery projects, where charge-changing modifications must be considered.