纳米尺度下水分子对DNA弹性行为影响的研究

The elastic properties of ds-DNA molecules are believed to play an important role in many biological functions, such as DNA replication, gene expression, and site-specific interactions between DNA and proteins. Over the past two decades, the elastic properties of single ds-DNA molecules have been extensively studied with the development of single molecule manipulation techniques. At present the experimental observation accuracy has been improved from hundreds to several bases. Water is essential to life, yet we still do not fully understand at the nanometer scale. Increasingly evident is it participation as an active matrix, not simply as a solvent. Almost all proteins and nucleic acids are inactive in the absence of water, and hydration determines their structural stability, flexibility, and the function. An understanding of the dynamics of water molecules at the surface of the elastic ds-DNA molecule is the goal of this project. Combining the molecular dynamic method and the discrete DNA elastic model, we will construct a simulation system to study the influence of water molecule to the elastic property of ds-DNA at the nanoscale. Firstly using the molecular dynamic method, we will simulate the water molecule distribution image at the ds-DNA surface under different elastic condition such as stretching, bending and radial compressing elasticity. The ds-DNA surface is complex, as many components are involved in the hydration at the interface. We will focus on the distribution difference of the different conformation such as the major and minor grooves, the different sequences such as Adenine, Thymine, Cytosine and Guanine. By the method of statistical physics and comparing with the experimental results, we analysis the difference and construct a discrete water interaction potential that is available for the discrete ds-DNA elastic model. We will construct a discrete water-DNA system to explore the influence of water molecule to the ds-DNA axis stretching property through a Langevin dynamic based computer simulation. The stretching property of ds-DNA has been exlored by single molecule manipulation techniques. Comparing with different experimental results, we can get the water influence to ds-DNA stretching elastic property, and understand the role of water molecule during the dynamic process. Based on this results, we will revise the simulation system and try to construct new systems to explore the influence of water molecule to the bending and the radial compression elastic property. We will simulate the bending persistent length of ds-DNA at the nanoscale, and analysis the influence of the water molecule and the ions to the bending persistent length. Comparing the simulation results and the experimental results, we will study the role of water molecule in the local bending rigidity and radial compression rigidity, which is expected to be helpful in better understanding the interaction between ds-DNA and protein, and their functions.

许多重要的生物学功能如DNA的复制、基因的表达及其与蛋白质的相互作用都涉及到DNA 的弹性行为。单分子和纳米技术的发展使单分子DNA弹性力学性质的研究成为热点。水作为活性基质，从不同角度参与生物活动中。本项目将结合分子动力学方法和离散化弹性模型动力学方法，在纳米尺度开展水对DNA弹性行为影响的动力学研究。首先用分子动力学方法结合实验结果，模拟水分子在拉伸和弯曲DNA分子片段周围的分布情况，以及水分子在不同序列情况下的分布情况；借鉴分子动力学方法模拟的水分子分布情况及功能，构建离散化DNA弹性模型中水分子的势能函数，建立水分子对DNA弹性力学影响研究的离散化模型系统。在此基础上，结合DNA的单分子实验数据，开展纳米尺度水分子对DNA拉伸弹性影响、弯曲及径向压弹性影响的理论计算和模拟。结合水分子实验数据，开展相应的结构功能信息研究及相应的生物学意义。

随着单分子和纳米实验技术的发展，掩盖在总体平均尺度内单个分子的行为可以通过单分子操纵方法展现出来，DNA在单分子尺度独特的弹性力学行为逐渐展现在人们的面前。理解和掌握DNA的力学性质有利于在单分子尺度研究DNA的生物学性质及其与蛋白质的相互作用。实验技术的发展，越来越多的证据表明水不仅承担溶剂的角色，而且作为活性基质从不同尺度参与生物活动中。本项目在分子层次讨论DNA的弹性力学行为以及水分子对DNA弹性行为的影响，初步建立了分子尺度结合量子力学DFT计算、分子动力学和离散化弹性模型动力学方法研究DNA力学行为的方法，获得了一些普适性规律。初步取得了以下进展：.局部DNA小片段的力学性质对于DNA的生物学功能和基于DNA的纳米机器的设计具有非常重要的意义，因此我们开展了小针尖下DNA压弹性的研究。随着针尖半径的减小，DNA的压弹性逐渐体现出结构信息。当针尖直径小于等于12纳米的时候，DNA的压弹性出现了一个快速的力转变过程。从氢键能量和碱基堆积作用能量的变化数据可以知道，在这个过程中发生了局部的解螺旋过程。在DNA解螺旋的过程中，首先会发生配对氢键的破裂，随着压弹性的积聚，位于针尖中心的DNA骨架开始从双螺旋结构解旋为一种平行结构。因此氢键和碱基堆积作用决定了小尺度DNA的压弹性。.结合量子化学、分子动力学方法和离散化DNA模型，我们研究了ssDNA与氧化石墨烯之间的相互作用。我们发现无论DNA放置的初始位置如何，ss-DNA可以稳定吸附在GO上的不同区域。但是由于氧化区域和非氧化区域交界处存在较强的边界势垒，大多数DNA最终会选择性全部或者部分吸附在氧化区域，非氧化区域吸附较少。从吸附过程的动力学分析可知，首先ss-DNA通过与氧化石墨烯表面的氧化基团之间的氢键作用拉近DNA与氧化石墨烯之间的距离，接着通过整体和局部构像的调整，在ssDNA的碱基和氧化石墨烯上的芳香环之间形成稳定的π-π堆积作用。我们详细分析了底层的物理机制：相比较于π-π堆积作用，氢键作用虽然弱但是它作用范程长，能够更快的接触氧化石墨烯面板；在形成π-π堆积作用时候，ssDNA需要更长的弛豫时间来调整自身的结构来与氧化石墨烯面板。这种协同的动力学过程对于目前基于DNA-氧化石墨烯的单分子检测、纳米药物设计和生物传感器的设计及实验理解具有重要的理论指导意义。