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

纽约大学的马克·塔克曼（Mark Tuckerman）获得了化学学部理论模型和计算方法项目的奖励，用于研究、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，以新颖的方式解决复杂化学过程中凝聚态的直接可测量的结构和动态量。为此，在经典正则配分函数中引入专门化变量变换的基础上，正在开发一种新的构象抽样方法。这种方法减少了能量势垒的影响，而不改变系统的热力学和平衡性质。应用包括越来越复杂的系统，从多肽到快速折叠的蛋白质。因此，从人类健康（模拟蛋白质折叠和缺失折叠）到新材料的合理设计等领域都有潜在的好处。该项目的第二个组成部分是通过量子力学/分子力学（QM/MM）方法研究酶等大型生物分子的化学反应性。建立了分子伪势的严格理论，用于描述量子力学子系统和量子力学子系统之间的相互作用。新的伪潜能将被收集在一个数据库中，并在获奖人的网站上提供给社区。方法论开发及其与社区免费提供的用户友好的开源软件的结合是该项目的组成部分，它对计算化学和生物学产生了强烈的影响，为解决计算机中的复杂问题带来了新的方法。塔克曼大学的本科生、研究生和博士后研究人员是一个多元化、性别平衡的群体。研究生统计力学课程的笔记，目前可通过网络获得，补充了本项目的进展。美国数学协会纽约分会数学演讲者局（MSB）举办的外展研讨会丰富了地区初中、高中、学院和大学的学生和教师的背景，讨论了超越传统数学课程的主题。

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.