Formaneck Mark S, Cui Qiang
Theoretical Chemistry Institute, Department of Chemistry, University of Wisconsin, Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA.
J Comput Chem. 2006 Dec;27(16):1923-43. doi: 10.1002/jcc.20489.
To investigate whether implicit solvent models are appropriate for mechanistic studies of conformational transition in proteins, a recently developed generalized Born model (GBSW) was applied to a small signaling protein, chemotaxis protein Y (CheY), with different combinations of the phosphorylation state and conformation of the system; the results were compared to explicit solvent simulations using a stochastic boundary condition. The subtle but distinct conformational transitions involved in CheY activation makes the system ideally suited for comparing implicit and explicit solvent models because these conformational transitions are potentially accessible in both types of simulations. The structural and dynamical properties analyzed include not only those localized to the active site region but also throughout the protein, such as sidechain methyl group order parameters, backbone hydrogen bonding lifetime and occupancy as well as principal components of the trajectories. Overall, many properties were well reproduced by the GBSW simulations when compared with the explicit solvent calculations, although a number of observations consistently point to the suggestion that the current parameterization of the GBSW model tends to overestimate hydrogen-bonding interactions involving both charged groups and (charge-neutral) backbone atoms. This deficiency led to overstabilization of certain secondary structural motifs and more importantly, qualitatively different behaviors for the active site groups (Thr 87, Ala 88, the beta4-alpha4 loop) in response to phosphorylation, when compared with explicit solvent simulations. The current study highlights the value of carrying out both explicit and implicit solvent simulations for complementary mechanistic insights in the analysis of conformational transition in biomolecules.
为了研究隐式溶剂模型是否适用于蛋白质构象转变的机理研究，将最近开发的广义玻恩模型（GBSW）应用于一种小信号蛋白——趋化蛋白Y（CheY），该系统具有不同的磷酸化状态和构象组合；并将结果与使用随机边界条件的显式溶剂模拟进行比较。CheY激活过程中涉及的微妙但明显的构象转变使该系统非常适合比较隐式和显式溶剂模型，因为这些构象转变在两种类型的模拟中都可能实现。分析的结构和动力学性质不仅包括那些局限于活性位点区域的性质，还包括整个蛋白质的性质，如侧链甲基基团序参量、主链氢键寿命和占有率以及轨迹的主成分。总体而言，与显式溶剂计算相比，GBSW模拟很好地再现了许多性质，尽管一些观察结果一致表明，GBSW模型目前的参数化倾向于高估涉及带电基团和（电荷中性）主链原子的氢键相互作用。这一缺陷导致某些二级结构基序过度稳定，更重要的是，与显式溶剂模拟相比，活性位点基团（Thr 87、Ala 88、β4-α4环）在磷酸化时的行为在性质上有所不同。当前的研究强调了在生物分子构象转变分析中进行显式和隐式溶剂模拟以获得互补机理见解的价值。
