Free-energy component analysis of 40 protein-DNA complexes: A consensus view on the thermodynamics of binding at the molecular level
Free-energy component analysis of 40 protein-DNA complexes: A consensus view on the thermodynamics of binding at the molecular level
复制标题
DOI：
10.1002/jcc.10009
复制
发表时间：
2002-01-15
影响因子：
3
通讯作者：
Beveridge, DL
中科院分区：
文献类型：
--
作者：
Jayaram, B;McConnell, K;Beveridge, DL
蛋白质与DNA上特定靶点的非共价结合--这是基因表达和调控的核心过程--迄今已被证明是特殊的，难以概括驱动力的性质。蛋白质-DNA复合体的大量结构信息为分子热力学的理论研究奠定了基础，旨在确定导致特定大分子识别的作用力。从结构信息出发，计算这种复杂体系的绝对结合自由能是一项艰巨的任务。采用最近在处理蛋白质和核酸中的原子水平相互作用(包括溶剂和盐效应)方面的一些进展，我们以唯象模式建立了一种能量组分方法，并服从于系统的改进，并开发了类似于40个代表各种结构基序和功能的蛋白质-DNA复合体中结合的自由能贡献者的计算第一图谱。我们的结果生动地说明了自由能分量的补偿性质，这些自由能分量有助于获得最佳结合的识别能量学，我们的结果明确地强调了填充、包括氢键在内的静电学、离子和水释放(空化)在蛋白质-DNA结合中所起的作用。空化和范德华贡献无一例外地有利于络合作用。从普遍的观点来看，静电学略微不利。蛋白质上的碱性残基有助于结合，尽管去溶解的费用很高。酸性残基和中性残基产生的静电不利于结合，与DNA短片段结合的包络模式有利于很强的不利净静电，但对范德华和空化贡献非常有利。因此，非共价蛋白质-DNA关联是这些不同竞争力量的系统特有的微妙平衡行为。随着应用于大分子识别的计算方法的进步，现在的挑战似乎是在药物设计中将差异(初始和最终)能量与取代基效应相关联，并从亲和力转向特异性。Z(C)2002 John Wiley&Sons，Inc.
Noncovalent association of proteins to specific target sites on DNA-a process central to gene expression and regulation-has thus far proven to be idiosyncratic and elusive to generalizations on the nature of the driving forces, The spate of structural information on protein-DNA complexes sets the stage for theoretical investigations on the molecular thermodynamics of binding aimed at identifying forces responsible for specific macromolecular recognition. Computation of absolute binding free energies for systems of this complexity transiting from structural information is a stupendous task. Adopting some recent progresses in treating atomic level interactions in proteins and nucleic acids including solvent and salt effects, we have put together an energy component methodology cast in a phenomenological mode and amenable to systematic improvements and developed a computational first atlas of the free energy contributors to binding in similar to 40 protein-DNA complexes representing a variety of structural motifs and functions. Illustrating vividly the compensatory nature of the free energy components contributing to the energetics of recognition for attaining optimal binding, our results highlight unambiguously the roles played by packing, electrostatics including hydrogen bonds, ion and water release (cavitation) in protein-DNA binding. Cavitation and van der Waals contributions without exception favor complexation. The electrostatics is marginally unfavorable in a consensus view. Basic residues on the protein contribute favorably to binding despite the desolvation expense. The electrostatics arising from the acidic and neutral residues proves unfavorable to binding, An enveloping mode of binding to short stretches of DNA makes for a strong unfavorable net electrostatics but a highly favorable van der Waals and cavitation contribution. Thus, noncovalent protein-DNA association is a system-specific fine balancing act of these diverse competing forces. With the advances in computational methods as applied to macromolecular recognition, the challenge now seems to be to correlate the differential (initial vs. final) energetics to substituent effects in drug design and to move from affinity to specificity. z (C) 2002 John Wiley & Sons, Inc.