Development and application of novel methods for enhanced conformational sampling, free energy prediction, and hybrid QM/MM calculations

纽约大学的Mark Tuckerman得到了化学部理论模型和计算方法项目的支持，负责研究、开发和应用增强构象采样、自由能预测和混合QM/MM计算的新方法。该项目的目的是在建模和模拟的基础上，以新的方式直接解决凝聚相中复杂化学过程的可测量的结构和动态量。为此，正在开发一种新的构象采样方法，该方法基于在经典正则配分函数中引入专门的变量变换。这种方法在不改变系统的热力学和平衡性质的情况下减少了势垒的影响。应用包括越来越复杂的系统，从多肽到快速折叠蛋白质。因此，从人类健康(模拟蛋白质折叠和错失折叠)到合理设计新材料，都有潜在的好处。该项目的第二个组成部分通过量子力学/分子力学(QM/MM)方法研究酶等大生物分子的化学反应。发展了一个严格的分子赝势理论来描述QM和MM子系统之间的相互作用。新的伪势将被收集到一个数据库中，供社区在获奖者的网站上使用。方法论的开发及其纳入社区免费提供的用户友好的开放源码软件是该项目的组成部分，这些内容对计算化学和生物学产生了重大影响，导致了解决硅胶复杂问题的新方法。塔克曼的本科生、研究生和博士后研究人员是一个多元化且性别平衡的群体。统计力学研究生课程的笔记，目前可在网上获得，并补充了本项目的进展。在美国数学协会纽约分部的数学演讲局(MSB)举办的外联研讨会，丰富了地区中学、高中、学院和大学的学生和教职员工关于传统数学课程以外的主题的背景。

Mark Tuckerman of New York University is supported by an award from the Theory Models and Computational Method program of the Chemistry Division to carry out research, development, and application of novel methods for enhanced conformational sampling, free energy prediction, and hybrid QM/MM calculations. The aim of this project is to address directly measurable structural and dynamical quantities of complex chemical processes in the condensed phase in novel ways based on modeling and simulation. To that end, a novel approach to conformational sampling based on the introduction of specialized variable transformations in the classical canonical partition function is being developed. This approach reduces the effect of energy barriers without altering thermodynamic and equilibrium properties of the system. Applications include systems with increasing complexity, from peptides to fast-folding proteins. Hence, there are potential benefits to fields ranging from human health (simulations of protein folding and miss-folding) to the rational design of novel materials. A second component of the project addresses chemical reactivity in large biomolecules such as enzymes via the quantum mechanical/molecular mechanical (QM/MM) method. A rigorous theory of molecular pseudo-potentials is developed for describing the interaction between the QM and MM subsystems. The new pseudo-potentials are to be gathered in a database made available to the community on the awardee's Web site. Methodology development and its incorporation into user-friendly open-source software that is freely available to the community are components of the project that strongly impact computational chemistry and biology, leading to new approaches for solving complex problems in silico. Tuckerman's undergraduate and graduate students and postdoctoral researchers are a diverse and gender-balanced group. Notes of the graduate Statistical Mechanics course, currently available through the Web, are supplemented with advances in this project. Outreach seminars at the Mathematics Speakers Bureau (MSB) of the New York section of the Mathematical Association of America enrich the background of students and faculty of regional middle schools, high schools, colleges and universities on topics reaching beyond the traditional math curriculum.