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首页> 美国卫生研究院文献>other >Computing Conformational Free Energy Differences in Explicit Solvent: An Efficient Thermodynamic Cycle using an Auxiliary Potential and a Free Energy Functional Constructed from the End Points
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Computing Conformational Free Energy Differences in Explicit Solvent: An Efficient Thermodynamic Cycle using an Auxiliary Potential and a Free Energy Functional Constructed from the End Points

机译：计算显式溶剂中的构象自由能差：使用辅助势和从端点构造的自由能函数的有效热力学循环

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摘要

Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: 1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and 2) the free energy difference between the open and closed conformations of β-cyclodextrin, a “host” molecule that serves as a model for molecular recognition in host-guest binding. β-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making β-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with 2 endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the β-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required.
机译：许多生物分子经历与变构或配体结合相关的构象变化。如果时间长，则很难在计算机仿真中观察这些变化。通过使用简单的哈密顿量观察辅助自由能面上的跃迁，并通过自由能计算将该自由能面连接到目标自由能面，可以加快这些计算的速度。在这里，我们表明可以用能量表示（ER）密度泛函近似代替循环的自由能分支。我们计算：1）丙氨酸二肽从右手自由能盆地向左手盆地转变的构象自由能变化，以及2）β-环糊精（一个“宿主”）的开放和封闭构象之间的自由能差在宿主-客体结合中充当分子识别模型的分子。 β-环糊精含有147个原子，而丙氨酸二肽为22个原子，这使β-环糊精成为一个大分子，可以通过自由能扰动或积分方法来计算溶剂化自由能，而最大的系统已将ER方法与精确自由度进行了比较。能量方法。 ER方法用2个端点模拟代替了28个模拟以计算每个耦合自由能，从而将丙氨酸二肽的计算时间减少了约70％，β-环糊精的计算时间减少了> 95％。即使在辅助自由能表面上的构象分布与目标自由能表面上的构象分布实质上不同时，该方法仍然有效，尽管这两个表面之间需要一定程度的重叠。

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