Absolute binding free energies: A quantitative approach for their calculation
Absolute binding free energies: A quantitative approach for their calculation
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DOI：
10.1021/jp0217839
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发表时间：
2003-09-04
影响因子：
3.3
通讯作者：
Karplus, M
中科院分区：
文献类型：
--
作者：
Boresch, S;Tettinger, F;Karplus, M
分析了基于自由能模拟的分子动力学（MD）计算绝对结合亲和力的方法，并给出了计算绝对结合亲和力的精确方法。获得聚合结果的关键是引入合适的辅助约束，以防止配体在天然配体-受体相互作用被炼金术关闭时离开结合位点。我们描述了一套通用的约束，(i)可用于MD模拟，（ii）限制配体的位置和方向，以及（iii）相对于受体而不是相对于空间中的固定点定义。免费能源成本。对于这组约束，a (r)可以用解析法求出。虽然这些技术最初是为气相开发的，但结果表达式是准确的，因为溶质-溶剂相互作用的所有贡献都与最终结果相抵消。δ a (r)的值仅取决于所选谐波约束项的平衡值和力常数，因此可以很容易地计算出来。研究了结合自由能的标准态依赖关系，表明本文的方法正确地考虑了这一点。通过计算苯与T4溶菌酶L99A突变体形成的络合物，数值验证了δ taa (r)的解析表达式。通过基于酪氨酸与酪氨酸- trna合成酶结合的简化模型的完整结合自由能计算来说明整个方法。结果证明了所提出的约束的有效性，并证实了所计算的束缚自由能与约束的细节无关。与先前计算束缚自由能的公式作了比较，并描述了该工作的某些局限性。分析了结合过程中δ a (r)与平动熵和旋转熵损失之间的关系。
The computation of absolute binding affinities by molecular dynamics (MD) based free energy simulations C, is analyzed, and an exact method to carry out such a computation is presented. The key to obtaining converged results is the introduction of suitable, auxiliary restraints to prevent the ligand from leaving the binding site when the native ligand-receptor interactions are turned off alchemically. We describe a versatile set of restraints that (i) can be used in MD simulations, that (ii) restricts both the position and the orientation of the ligand, and that (iii) is defined relative to the receptor rather than relative to a fixed point in space. The free energy cost. DeltaA(r), for this set of restraints can be evaluated analytically. Although the techniques were originally developed for the gas phase, the resulting expression is exact, since all contributions from solute-solvent interactions cancel from the final result. The value of DeltaA(r) depends only on the equilibrium values and force constants of the chosen harmonic restraint terms and, therefore, can be easily calculated. The standard state dependence of binding free energies is also investigated, and it is shown that the present approach takes this into account correctly. The analytical expression for DeltaA(r) is verified numerically by calculations on the complex formed by benzene with the L99A mutant of T4 lysozyme. The overall approach is illustrated by a complete binding free energy calculation for a complex based on a simplified model for tyrosine bound to tyrosyl-tRNA-synthetase. The results demonstrate the usefulness of the proposed set of restraints and confirm that the calculated binding free energy is independent of the details of the restraints. Comparisons are made with earlier formulations for the calculation of binding free energies, and certain limitations of that work are described. The relationship between DeltaA(r) and the loss of translational and rotational entropy during a binding process is analyzed.