Chong Song-Ho, Ham Sihyun
Department of Chemistry, Sookmyung Women's University , Cheongpa-ro 47-gil 100, Yongsan-Ku, Seoul 04310, Korea.
J Chem Theory Comput. 2016 Jun 14;12(6):2509-16. doi: 10.1021/acs.jctc.6b00174. Epub 2016 May 13.
Molecular recognition through the noncovalent association of biomolecules is of central importance in biology and pharmacology. Developing reliable computational methods for estimating binding thermodynamic parameters is therefore of great practical value. However, considerable uncertainty remains regarding the external entropy that is associated with the reduction in the external (positional and orientational) degrees of freedom upon complex formation. Here, we present a novel statistical mechanical method for computing the external entropy by extending the energetic approach we have developed for unimolecular processes to association processes. We find that, in contrary to what is postulated in most of the previous methods, intrinsic couplings between the internal and external degrees of freedom of bound complex cannot in general be neglected in the determination of the external entropy. Nevertheless, there exists the best choice of the external coordinates with which those couplings are minimized. With such a choice of the external coordinates, the lowest upper bound of the external entropy is obtained from a tractable expression, which serves as an estimate of the external entropy. Our method can be implemented in a straightforward manner with molecular dynamics simulations, and its applicability is demonstrated through the application to the barnase-barstar complex.
通过生物分子的非共价缔合进行分子识别在生物学和药理学中至关重要。因此，开发可靠的计算方法来估算结合热力学参数具有很大的实用价值。然而，关于与复合物形成时外部（位置和取向）自由度降低相关的外部熵，仍存在相当大的不确定性。在此，我们提出一种新颖的统计力学方法，通过将我们为单分子过程开发的能量方法扩展到缔合过程来计算外部熵。我们发现，与大多数先前方法所假定的情况相反，在确定外部熵时，结合复合物内部和外部自由度之间的内在耦合通常不能被忽略。然而，存在使这些耦合最小化的外部坐标的最佳选择。通过这样选择外部坐标，可以从一个易于处理的表达式中获得外部熵的最低上限，该表达式可作为外部熵的估计值。我们的方法可以通过分子动力学模拟以直接的方式实现，并通过应用于巴纳酶 - 巴纳斯塔复合物来证明其适用性。
