Overcoming dissipation in the calculation of standard binding free energies by ligand extraction.
Overcoming dissipation in the calculation of standard binding free energies by ligand extraction.
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DOI：
10.1002/jcc.23398
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发表时间：
2013-10-15
影响因子：
3
通讯作者：
Gilson, Michael K.
中科院分区：
文献类型：
--
作者：
Velez-Vega, Camilo;Gilson, Michael K.
关键词：
本文讨论了计算结合的标准自由能的分子模拟中，结合的配体被提取从其结合位点的转向分子动力学（MD）模拟或平衡伞采样。主客体系统被用作测试床，以检查获得配体萃取的可逆功的要求。我们发现，无论是转向MD和伞采样，显着的不可逆性可以发生时，客体分子越过能量障碍，突然跳到一个新的位置，导致存储在拉伸分子的能量耗散。对于柔性分子，即使采用刚性拉伸弹簧也会发生这种情况，并且在弹簧通过单个固定附着点附着到分子的计算中难以抑制。因此，我们介绍和测试的方法，波动引导拉动（FGP），自适应地调整弹簧的附着点的基础上，客人的原子波动相对于主机。这种自适应方法被发现，大大提高了本系统的操纵MD和伞采样计算的可逆性。然后使用的结果来估计标准结合自由能在一个全面的框架内，被称为附着-拉动-释放（APR），它认识到，结合的标准自由能必须不仅包括拉动工作本身，而且还连接的工作，然后释放弹簧，其中释放工作包括一个会计的标准浓度的配体被排出。
This paper addresses calculations of the standard free energy of binding from molecular simulations in which a bound ligand is extracted from its binding site by steered molecular dynamics (MD) simulations or equilibrium umbrella sampling. Host-guest systems are used as test beds to examine the requirements for obtaining the reversible work of ligand extraction. We find that, for both steered MD and umbrella sampling, marked irreversibilities can occur when the guest molecule crosses an energy barrier and suddenly jumps to a new position, causing dissipation of energy stored in the stretched molecule(s). For flexible molecules, this occurs even when a stiff pulling spring is employed, and it is difficult to suppress in calculations where the spring is attached to the molecules by single, fixed attachment points. We therefore introduce and test a method, Fluctuation-Guided Pulling (FGP), which adaptively adjusts the spring's attachment points based on the guest's atomic fluctuations relative to the host. This adaptive approach is found to substantially improve the reversibility of both steered MD and umbrella sampling calculations for the present systems. The results are then used to estimate standard binding free energies within a comprehensive framework, termed attach-pull-release (APR), which recognizes that the standard free energy of binding must include not only the pulling work itself, but also the work of attaching and then releasing the spring, where the release work includes an accounting of the standard concentration to which the ligand is discharged.
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