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

纽约大学的Mark塔克曼获得了化学部理论模型和计算方法项目的奖励，以进行增强构象采样，自由能预测和混合QM/MM计算的新方法的研究，开发和应用。该项目的目的是解决直接可测量的结构和动态量的复杂化学过程中的凝聚相在新的方式基于建模和仿真。为此，一种新的方法，构象采样的基础上引入专门的变量变换的经典正则配分函数正在开发中。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能量势垒的影响。应用包括从肽到快速折叠蛋白质等复杂性不断增加的系统。因此，从人类健康（蛋白质折叠和错误折叠的模拟）到新材料的合理设计等领域都有潜在的好处。 该项目的第二部分通过量子力学/分子力学（QM/MM）方法解决大生物分子（如酶）的化学反应性。本文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。新的伪潜力将被收集在一个数据库中，该数据库将在获奖者的网站上提供给社区。方法论开发及其纳入向社区免费提供的用户友好的开源软件是该项目的组成部分，对计算化学和生物学产生了强烈影响，从而为解决计算机模拟复杂问题带来了新的方法。塔克曼的本科生和研究生以及博士后研究人员是一个多元化和性别平衡的群体。研究生统计力学课程的笔记，目前可通过网络获得，补充了这个项目的进展。在美国数学协会纽约分部的数学演讲者局（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师的背景，主题超出了传统的数学课程。

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.