基于静电多极势的B-DNA粗粒化模型的发展和应用

Currently, all-atom (AA) dynamics simulation (MD) has been proved to be very useful in studying the DNA systems, which attracts a lot of attention in the field of molecular biology. However, due to high computational cost, it is greatly challenging for AA MD to study the DNA-relevant processes occurring at microsecond level or above. DNA is a highly-charged polyelectrolyte and the electrostatic interaction plays an important role in DNA simulations. Here, based on the electric multipole potential (EMP), we will develop a generic CG model for B-DNA structure, coupling with existing polarizable water and ion models, namely a DNA-EMP force field (FF). Based on available experimental and AA data, validation of the DNA-EMP FF will be assessed by simulating a set of medium structures. Then the roles that electrostatic interaction, polarizable water and ions play in stabilizing the duplex formation of B-DNA will be discussed by the DNA-EMP FF. Interestingly, by adding a spherical confinement potential in the DNA-EMP FF, conformational changes of DNA in cell nucleus or viral capsid can be studied in the virtual sphere. Furthermore, combining the DNA-EMP FF with the existing TMFF protein model, allosteric dynamics of histone-DNA systems can be studied with the EMP. Besides, a local-frame strategy will be adopted to achieve the back mapping from CG configuration to AA representation.

目前，通过全原子模拟来研究DNA分子实验现象的机理是分子生物学领域的研究热点之一。然而由于计算量过大，全原子动力学模拟在研究发生在微秒以上的DNA变构现象方面面临挑战。而DNA分子作为高带电聚合电解质，静电作用在DNA相关动力学中起着重要作用。结合现有的极化水和离子模型，本项目拟发展新的基于静电多极势的B-DNA粗粒化力场模型（称为DNA-EMP力场），并进行有效性检测。新力场将用于阐明溶质静电作用在维系B-DNA双螺旋结构中的作用以及水分子和离子对B-DNA不同基团的作用机理。新的力场将应用于以下方面：1）在新力场中引入球形限制势，以阐明生物膜对内部B-DNA分子折叠变构的影响；2）将新力场与粗粒化蛋白模型TMFF力场结合，以揭示组蛋白-DNA在静电多极势下变构的机理。此外，本项目还将采用局部坐标系方法建立DNA由粗粒化模型到全原子模型的转换，实现DNA的结构重构。

静电作用在DNA分子动力学模拟中起着重要作用。 本课题意将静电多极变量引入到B-DNA粗粒化力场中，以提高DNA粗粒化模拟中对静电作用的描述。首先我们对粗粒化极化水分子力场进行深入探讨，分别将5、4~10个水分子构造为单个携带静电多极或静电极化的粗粒化“分子”，进行纯水体系的参数拟合及重要特征预测。之后我们还对水分子的超粗粒化模型进行初步探究—将20~500个水分子视作单个粗粒化单元。系列水分子粗粒化模型的发展可直接为其他生物分子粗粒化力场提供一显性溶剂环境。为研究静电极化作用对DNA动力学结构(氢键、groove以及结构稳定性)的影响，我们还将有效可极化键(EPB)模型引入到现有DNA原子力场中。结果表明，跟传统力场相比，浮动电荷模型的加入在一定程度上减弱了碱基对的氢键作用，并增加了B-DNA体系的 major/minor groove宽度。此外，我们还提出RF-LF方法，实现蛋白质由粗粒化模型到全原子结构的重构，为其他粗粒化模型到全原子重构提供一定参考。通过对基于静电极化或多极的模型发展，进一步明确静电作用在高带电性DNA体系中重要作用。

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