Hamelberg Donald, Shen Tongye, McCammon J Andrew
Howard Hughes Medical Institute, Center for Theoretical Biological Physics, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093-0365, USA.
J Am Chem Soc. 2005 Feb 16;127(6):1969-74. doi: 10.1021/ja0446707.
The presence of serine/threonine-proline motifs in proteins provides a conformational switching mechanism of the backbone through the cis/trans isomerization of the peptidyl-prolyl (omega) bond. The reversible phosphorylation of the serine/threonine modulates this switching in regulatory proteins to alter signaling and transcription. However, the mechanism is not well understood. This is partly because cis/trans isomerization is a very slow process and, hence, difficult to study. We have used our accelerated molecular dynamics method to study the cis/trans proline isomerization, preferred backbone conformation of a serine-proline motif, and the effects of phosphorylation of the serine residue. We demonstrate that, unlike normal molecular dynamics, the accelerated molecular dynamics allows for the system to escape very easily from the trans isomer to cis isomer, and vice versa. Moreover, for both the unphosphorylated and phosphorylated peptides, the statistical thermodynamic properties are recaptured, and the results are consistent with experimental values. Isomerization of the proline omega bond is shown to be asymmetric and strongly dependent on the psi backbone angle before and after phosphorylation. The rates of escape decrease after phosphorylation. Also, the alpha-helical backbone conformation is more favored after phosphorylation. This accelerated molecular dynamics approach provides a general approach for enhancing the conformational transitions of molecular systems without having prior knowledge of the location of the minima and barriers on the potential-energy landscape.
蛋白质中丝氨酸/苏氨酸 - 脯氨酸基序的存在，通过肽基 - 脯氨酰（ω）键的顺反异构化提供了一种主链的构象转换机制。丝氨酸/苏氨酸的可逆磷酸化调节调节蛋白中的这种转换，以改变信号传导和转录。然而，该机制尚未得到很好的理解。部分原因是顺反异构化是一个非常缓慢的过程，因此难以研究。我们使用加速分子动力学方法来研究脯氨酸的顺反异构化、丝氨酸 - 脯氨酸基序的优选主链构象以及丝氨酸残基磷酸化的影响。我们证明，与正常分子动力学不同，加速分子动力学使系统能够非常容易地从反式异构体转变为顺式异构体，反之亦然。此外，对于未磷酸化和磷酸化的肽，统计热力学性质都能被重现，并且结果与实验值一致。脯氨酸ω键的异构化显示出不对称性，并且强烈依赖于磷酸化前后的ψ主链角。磷酸化后逃逸速率降低。而且，磷酸化后α - 螺旋主链构象更受青睐。这种加速分子动力学方法提供了一种通用方法，用于增强分子系统的构象转变，而无需事先了解势能面上最小值和势垒的位置。
