Free Energies in Biomolecular Systems: Development and Applications of Theoretical and Computational Approaches

在原子水平上，生物学基本上是由各种不同分子的活动和相互作用控制的。有些，如蛋白质和核酸，是大的和高度复杂的化学结构称为大分子。其他是小的化合物，可以像单个水分子一样简单。关于活细胞中任何分子的最基本问题之一是它们相互作用和相互关联的方式。分子如何识别和结合特定的伴侣在生物学中起着关键作用。例如，这是生物“信号”和信息在活细胞内和活细胞之间传输和交流的方式之一，以及特定过程如何被触发和同步。该研究项目包括改进理论和计算方法，以准确计算和预测分子如何相互结合。根据统计热力学理论，控制分子缔合的量是“结合自由能”。这个数学上定义明确的量可以使用感兴趣分子的原子模型的计算机模拟来计算。其中一种方法被称为“分子动力学”模拟，可以帮助阐明在原子水平上控制生物分子结合的基本原理。这一领域的努力具有巨大的智力价值，因为生物学正在进入一个定量时代，需要预测分子结合的能力。这项研究是在学术环境中进行的，其更广泛影响的一个重要方面是教育和培训高素质的人才。参与研究项目的学生和博士后研究人员最终将进入就业市场，无论是在学术界还是在工业界，他们的先进技能将有助于社会的活力。此外，提高使用计算准确预测结合的能力具有巨大的实用价值，预计将对生物学和化学中的大量基本问题产生广泛的影响。例如，这一领域的技术进步可用于设计和设计更好的方法来检测、捕获和提取环境中的有毒分子（生物修复）。最后，研究产生的所有新知识以理论、解释和计算机程序的形式通过PI的实验室网站免费传播，以造福整个社区。

Biology, at the atomic level, is fundamentally controlled by the activity and interactions of a wide range of different molecules. Some, such as proteins and nucleic acids, are large and highly complex chemical structures called macromolecules. Others are small chemical compounds, which can be as simple as a single water molecule. One of the most basic questions about any of the molecules in the living cell is the manner by which they interact and associate with one another. How molecules recognize and bind to a specific partner plays a key role in biology. For example, this is one of the ways biological "signals" and information are transmitted and communicated within and between living cells, and how specific processes are triggered and synchronized. The research project consists in improving the theoretical and computational methods to calculate and predict accurately how molecules bind to one another. According to the theory of statistical thermodynamics, the quantity that controls the association of molecules is the "binding free energy". This mathematically well-defined quantity can be calculated using computer simulations of atomic models of the molecules of interest. One method, which is called "molecular dynamics" simulation, can help elucidate the fundamental principles governing the binding of biological molecules at the atomic level. Efforts in this area have great intellectual merit because biology is entering a quantitative era that requires an ability to predict the binding of molecules.This research is carried out in an academic environment and one essential aspect to the broader impact is the education and training of highly qualified personnel. The students and postdoctoral researchers involved in the research project will ultimately join the job market, either in academia or in industry, and their advanced skills will contribute to the vitality of society. Furthermore, improving the ability to predict binding accurately using computations has great pragmatic value and is expected to have a broad impact on a vast array of fundamental problems in biology and chemistry. For example, technological advances in this area could be used to engineer and design better method to detect, capture, and extract toxic molecules from the environment (bioremediation). Lastly, all the new knowledge produced by the research in the form of theories, explanation, and computer programs is freely disseminated via the PI's lab web site for the benefit of the entire community.