Quantifying and Designing for Electrostatic Preorganization in Enzymes

酶是促进或催化所有生物生命所需的化学反应的基本蛋白质分子。有了这个奖项，化学部门的生命过程化学项目将资助加州大学洛杉矶分校的Anastassia Alexandrova博士和科罗拉多矿业学院的Mark Eberhart博士，研究由数千甚至数万个原子组成的整个蛋白质分子是如何产生局部电场的，从而使酶能够作为高效和特定的催化剂发挥作用。这种作用在酶的活性位点，被称为静电预组织，是通过量子力学工具检测到的。对静电预组织的理解和这些量子力学工具的发展被应用于设计具有增强催化功能的人工酶。由此产生的人工酶在疾病预防、化学工业生产和环境修复方面具有潜在的重要意义。此外，该项目还通过一项名为“看到化学键”的倡议，促进了高中科学教师的专业发展和培训。这一倡议在课堂环境中使用视觉和量子力学技术，为化学键的重要概念提供实质内容，尽管人们通常对化学键的理解很差。本提案发展量子力学严格的计算技术来探测静电预组织，并评估其对天然和人工酶的熟练程度的影响。将扩展分子原子量子理论（QTAIM）并结合动力学模拟，以确定全蛋白质结构对酶活性位点电荷密度（rho）的扰动影响。使用这些探针跟踪人工酶的定向进化，同时询问预组织的进展。这些研究检测了酶进化到何种程度以改善远程静电。从这些计算研究中得出的见解允许通过远程突变战略性地改善静电，将预组织整合到酶设计中，并通过实验验证了预测。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Enzymes are essential protein molecules that facilitate or catalyze the chemical reactions required for life in all organisms. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Anastassia Alexandrova from the University of California, Los Angeles, and Dr. Mark Eberhart from the Colorado School of Mines to investigate how the entirety of the protein molecule, consisting of thousands or even tens of thousands of atoms, creates local electric fields that allow enzymes to function as highly efficient and specific catalysts. This effect at the enzyme's active site, called electrostatic preorganization, is detected through quantum mechanical tools. The understanding of electrostatic preorganization and the development of these quantum mechanical tools are applied to engineer artificial enzymes with enhanced catalytic functions. The resulting artificial enzymes are potentially important in disease prevention, industrial production of chemicals, and environmental remediation. In addition, the project promotes professional development and training of high school science teachers through an initiative called "See the chemical bond". This initiative uses visual and quantum mechanically enabled techniques in a classroom setting to give substance to the important though often poorly understood concept of chemical bonds.This proposal develops quantum-mechanically rigorous computational techniques to probe electrostatic preorganization, and assesses its effect on the proficiency of both natural and artificial enzymes. An extension of the Quantum Theory of Atoms in Molecules (QTAIM) in conjunction with dynamics simulations will be developed to determine the perturbative influence of the full protein structure to the charge density (rho) in an enzyme's active site. The directed evolution of artificial enzymes are followed using these probes, while interrogating the progression of preorganization. These studies detect the extent to which enzymes evolve toward improved long-range electrostatics. The insight resulting from these computational investigations allow integration of preorganization into enzyme design by strategically improving electrostatics through remote mutations, with the predictions tested experimentally.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.