Quantum Chemical Evaluation of Inter- and Intra-molecular Interactions in Proteins

该项目的总体目标是利用现代量子化学，为生物分子系统中的分子间和分子内相互作用提供准确和独特的见解，使用溶剂的连续体表示。线性标度半经验分而治之算法结合标准泊松-玻尔兹曼理论将应用于生物学相关问题，以研究蛋白质分子间和分子内相互作用。将采用经典的量子力学模拟和单点量子力学计算来估计蛋白质的介电常数。将进一步发展泊松-玻尔兹曼电荷转移方法以纳入电荷转移效应。在蛋白质和多肽中产生的线圈和盐桥相互作用的实验信息将用于验证该方法。鉴于计算机硬件和求解薛定谔方程的数值算法的进步，量子化学现在可以在全原子水平上为我们对大分子结构和功能的理解做出实际贡献。与经典方法相比，现代量子化学方法具有以下几个优点：(1)静电表示更准确，因为与经典模型不同，环境、构象、极化和电荷转移效应被明确地包括在内。(2)由于介质弛豫已明确地包含在QM模型中，因此不需要定义介电常数。(3)量子化学方法可以改进的方法已经被彻底地记录下来（即，在基集中包含相关性和改进）。该项目将对新型量子力学方法的发展产生广泛的影响，这些方法可以应用于重要的生物学问题。该研究项目将训练学生在形式理论，计算机编程，生物结构和手稿准备/出版。学生还将有机会与宾夕法尼亚州立大学以及美国和国外其他大学的其他生物小组进行互动。事实上，每个学生将被要求每年至少参加一次国家或国际会议，以海报或口头形式展示他/她的成果。已经建立了一个量子生物信息学数据库（QDB: http://qbiodb.chem.psu.edu/），这将有助于传播和分析这项工作的结果。本研究由化学学部的理论与计算化学项目和分子与细胞生物科学部的分子生物物理项目共同资助。

The overall goal of this project is to use modern quantum chemistry to provide accurate and unique insights into inter and intramolecular interactions in biomolecular systems, using a continuum representation for the solvent. The linear-scaling semi empirical divide and conquer algorithm coupled with standard Poisson-Boltzmann theory will be applied to biologically relevant problems to study inter and intramolecular interactions in proteins. Classical MD simulations and single point QM calculations will be carried out to estimate the value of the dielectric constant of a protein. The Poisson-Boltzmann charge transfer approach for the incorporation of charge transfer effects will be further developed. Experimental information generated on coiled-coil and salt bridge interactions in proteins and peptides will be used to validate the approach. Given the advances in computer hardware and in numerical algorithms for the solution of the Schrodinger equation, quantum chemistry can now realistically contribute at the all-atom level to our understanding of macromolecular structure and function. Modern quantum chemical approaches offer several advantages over classically based methods: (1)The electrostatic representation is more accurate because environmental, conformational, polarization and charge transfer effects are explicitly included unlike classical models. (2) There is no need to define the dielectric constant because dielectric relaxation is explicitly included in QM models. (3) The ways in which quantum chemical methods can be improved have been thoroughly documented (i.e., inclusion of correlation and improvements in the basis set). This project will have a broad impact on the development of novel quantum mechanical approaches that can be applied to important biological problems. The research project will train students in formal theory, computer programming, biological structure and manuscript preparation/publication. The students will also have the opportunity to interact with other biological group at Penn State and at other universities in the USA and abroad. Indeed, each student will be required to attend at least one national or international meeting per year to present his/her results in either a poster or oral format. A quantum bioinformatics database (QDB: http://qbiodb.chem.psu.edu/) has been created, which will aid in the dissemination and analysis of results from this work. This work is funded jointly by the Theoretical and Computational Chemistry Program in the Chemistry Division and the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences.