Department of Chemistry and The Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30302-4098, USA.
J Phys Chem B. 2009 Dec 31;113(52):16590-5. doi: 10.1021/jp907388m.
Improving the accuracy of molecular mechanics force field parameters for atomistic simulations of proteins and nucleic acids has been an ongoing effort. The availability of computer power and improved methodologies for conformational sampling has allowed the assessment of these parameters by comparing the free energies calculated from molecular dynamic (MD) simulations and those measured from thermodynamic experiments. Here, we focus on testing and optimizing the AMBER force field parameters for the omega dihedral, which represents rotation around the peptide bond of proteins. Due to the very slow isomerization rate of the peptide bond, it is not possible to sample the phase space with standard MD simulations. We therefore employed an accelerated MD method in explicit water in which the original Hamiltonian is modified to speed up conformational sampling and the correct canonical distribution is recaptured. Using well-studied model systems for the peptide and peptidyl prolyl bonds, we discovered that the AMBER omega dihedral parameters underestimated experimentally measured activation free energy barriers for cis/trans conversion as well as failed to reproduce the free energy difference between the two isomers. We reoptimized the original AMBER omega dihedral parameters and further validated their transferability on several experimentally studied dipeptides. The revised set of parameters successfully reproduced the cis/trans equilibria and free energy barriers within experimental and simulation errors. We also investigated the structures of the transition state and cis/trans isomers of prolyl peptide bonds in terms of pyramidality, a measure of the puckering of the prolyl ring. We observed, as expected from quantum mechanical studies, significant bidirectional, out-of-plane motions of prolyl nitrogen in the transition state.
改进用于蛋白质和核酸原子模拟的分子力学力场参数的准确性一直是一项持续的努力。计算机能力的提高和构象采样方法的改进，使得可以通过比较从分子动力学（MD）模拟计算的自由能和从热力学实验测量的自由能来评估这些参数。在这里，我们专注于测试和优化 AMBER 力场参数的 omega 二面角，该参数代表蛋白质中肽键的旋转。由于肽键的异构化速率非常慢，因此不可能用标准 MD 模拟来采样相空间。因此，我们采用了一种显式水中的加速 MD 方法，其中修改了原始哈密顿量以加快构象采样并重新捕获正确的正则分布。使用研究充分的肽和肽基脯氨酸键模型系统，我们发现 AMBER omega 二面角参数低估了实验测量的顺/反转换的活化自由能垒，并且无法重现两种异构体之间的自由能差。我们重新优化了原始的 AMBER omega 二面角参数，并进一步在几个经过实验研究的二肽上验证了它们的可转移性。修订后的参数集成功地在实验和模拟误差内重现了顺/反平衡和自由能垒。我们还研究了脯氨酸肽键的过渡态和顺/反异构体的结构，用金字塔度来衡量脯氨酸环的翘曲程度。我们观察到，正如量子力学研究所预期的那样，过渡态中脯氨酸氮的双向、面外运动非常明显。
