Direct estimation of entropy loss due to reduced translational and rotational motions upon molecular binding
Direct estimation of entropy loss due to reduced translational and rotational motions upon molecular binding
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DOI：
10.1002/bip.20344
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发表时间：
2005-12-05
期刊：
影响因子：
2.9
通讯作者：
Wong, CF
中科院分区：
文献类型：
--
作者：
Lu, BZ;Wong, CF
几十年来，由于结合而失去平移和转动(T-R)自由度所造成的熵成本已经得到了很好的认识。紧密结合的配体比松散结合的配体具有更高的熵成本。然而，量化配体结合后的剩余T-R运动并不是一件容易的事情。我们描述了一种方法，该方法使用一个简化的海森矩阵来估计由于平移和转动自由度对分子结合时的熵变化的贡献。计算使用了束缚态的谐和模型，但仅包括T-R自由度。这种近似大大加快了熵计算的速度，因为只需要处理6×6物质，这使得它更容易用于研究许多配体的计算机辅助药物设计。文中还讨论了与其他方法的方法学联系。我们测试了这一近似，并将其应用于研究ATP、多肽抑制剂(PKI)和几个结合水分子与蛋白激酶A(PKA)的结合。这些配体的大小范围很大。该模型对结合配体或水分子的剩余T-R熵给出了合理的估计。剩余T-R熵的取值范围很广，如PKA结合水分子的T-R熵为4~16卡/K(？)摩尔。(C)2005年威利期刊公司。
The entropic cost due to the loss of translational and rotational (T-R) degree of freedom upon binding has been well recognized for several decades. Tightly bound ligands have higher entropic costs than loosely bound ligands. Quantifying the ligand's residual T-R motions after binding, however, is not an easy task. We describe an approach that uses a reduced Hessian matrix to estimate the contributions due to translational and rotational degrees of freedom to entropy change upon molecular binding. The calculations use a harmonic model for the bound state but only include the T-R degrees of freedom. This approximation significantly speeds up entropy calculations because only 6 x 6 matt-ices need to be treated, which makes it easier to be used in computer-aided drug design for studying many ligands. The methodological connection with other methods is discussed as well. We tested this approximation by applying it to study the binding of ATP, peptide inhibitor (PKI), and several bound water molecules to protein kinase A (PKA). These ligands span a wide range in size. The model gave reasonable estimates of the residual T-R entropy of bound ligands or water molecules. The residual T-R entropy demonstrated a wide range of values, e.g., 4 to 16 cal/K(.)mol for the bound water molecules of PKA. (c) 2005 Wiley Periodicals, Inc.