WATER IN BIOLOGICAL SYTEMS

我们希望继续研究溶剂的性质和作用， 生物系统。 根据《公约》进行的工作的自然顺序 本期赠款是小分子蛋白质的研究 交互. 因此，我们计划推广和扩展这些研究 所有负责分子生物识别的因素 这种类型的互动所代表的水平。 小分子蛋白质 认知是许多药物作用、激素反应、神经 突触功能和酶催化与调节。 我们建议 对一个结构和性能良好的 特征的情况下，抑制剂与溶菌酶的结合，目的是 在分子水平上实现理解， 直接应用于设计酶抑制剂， 毒品 建立了溶剂模拟和分析方法， 目前的资助期将用于研究溶剂的变化， 酶和抑制剂之间的反应。 提出的问题 这里将是：溶剂行为如何有助于焓， 结合熵 溶质产生环境的哪些方面 对这种行为负责吗 溶剂的筛选效果如何 蛋白质-配体相互作用的结构？ 这最后一点与一个 研究蛋白质和配体的诱导作用将 回答这个长期存在的问题，什么是有效的电介质， 互动？ 装订图片将通过计算完成 配体和蛋白质之间的成对原子-原子相互作用的能量， 特别注意其有效射程;调查 与复合物形成时的构象变化相关的能量;以及 振动的正常模式的自由能的比较， 蛋白质在存在和不存在配体的情况下。 这最后一步的目的是 为了阐明低频“呼吸”模式在实验中的作用， 观察到的熵变

We desire to continue our studies of the nature and role of solvent in biological systems. A natural sequence of the work carried under the current period of the grant is the study of small molecule-protein interactions. We are thus planning to generalize and extend these studies to all the factors responsible for biological recognition at the molecular level as represented by this type of interaction. Small molecule-protein recognition is at the centre of much drug action, hormone response, nerve synapse function and enzyme catalysis and regulation. We propose to undertake a theoretical study of a structurally and thermodynamically well characterized case, the binding of inhibitors to lysozyme, with the aim of achieving understanding at the molecular level which in particular will be of direct application to the design of enzyme inhibitors which act as drugs. The methods of solvent simulation and analysis established during the current grant period will be used to study solvent changes on complex formation between the enzyme and an inhibitor. The questions addressed here will be: how does solvent behavior contribute to the enthalpy and entropy of binding? What aspects of the solute created environment are responsible for this behavior? What is the screening effect of the solvent structure on protein-ligand interactions? This last point together with an investigation of the induction effects in the protein and ligand will answer the long standing question, what is effective dielectric for such interactions? The picture of binding will be completed by calculation of the energy of pairwise atom-atom interactions between ligand and protein, with particular attention paid to their effective range; investigation of the energy associated with conformational change on complex formation; and comparison of the free energy of the normal modes of vibration of the protein in the present and absence of ligand. This last step is intended to clarify the role of low frequency 'breathing' modes in the expermentally observed entropy change.