Estimating kinetic rates from accelerated molecular dynamics simulations: Alanine dipeptide in explicit solvent as a case study

被引:41
作者
De Oliveira, Cesar Augusto F. [1 ]
Hamelberg, Donald
McCammon, J. Andrew
机构
[1] Univ Calif San Diego, Howard Hughes Med Inst, Ctr Theoret Biol Phys, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
D O I
10.1063/1.2794763
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Molecular dynamics (MD) simulation is the standard computational technique used to obtain information on the time evolution of the conformations of proteins and many other molecular systems. However, for most biological systems of interest, the time scale for slow conformational transitions is still inaccessible to standard MD simulations. Several sampling methods have been proposed to address this issue, including the accelerated molecular dynamics method. In this work, we study the extent of sampling of the phi/psi space of alanine dipeptide in explicit water using accelerated molecular dynamics and present a framework to recover the correct kinetic rate constant for the helix to beta-strand transition. We show that the accelerated MD can drastically enhance the sampling of the phi/psi conformational phase space when compared to normal MD. In addition, the free energy density plots of the phi/psi space show that all minima regions are accurately sampled and the canonical distribution is recovered. Moreover, the kinetic rate constant for the helix to beta-strand transition is accurately estimated from these simulations by relating the diffusion coefficient to the local energetic roughness of the energy landscape. Surprisingly, even for such a low barrier transition, it is difficult to obtain enough transitions to accurately estimate the rate constant when one uses normal MD.
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页数:8
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