Theoretical Bioorganic Chemistry

耶鲁大学的William Jorgensen获得了理论和计算化学计划的奖项，以开展半经验量子力学（SQM）技术的发展研究，用于模拟有机反应。为了使常规的计算研究的有机和酶的反应在溶液中，改进的SQM方法正在开发中。包括以前被忽视的“泡利”排斥和添加的d-轨道预计将产生更强的结果，特别是构象的能量变化和障碍，氢键，小环化合物，和反应的活化能的描述。新的SQM方法被应用在QM/MM计算的许多有机反应在溶液中，表现出显着的溶剂效应，其速度。这包括亲核取代、酰化、门舒特金反应、脱羧和[2，3] σ迁移重排。对于一般的反应研究，也有必要将组态相互作用（CI）纳入QM框架。这是追求使用对激发CI方法与最初的应用程序，溶剂分解反应和伯格曼环化。在所有情况下，SQM和CI计算都是在溶液中反应的MC模拟中实时进行的。最近发展起来的CRA（协同旋转与可变键角）方法将用于MC模拟进行从头折叠的多肽。在这种情况下，模拟方案的优化和对小蛋白的应用是优先项目。相关研究旨在预测和优化催化不对称反应的肽的结构，例如，反应的速率对于镜像基底是不同的。预计这项工作将对有机反应机理的概念理解产生广泛的影响。

William Jorgensen of Yale University is supported by an award from the Theoretical and Computational Chemistry program to carry out research on the development of semi-empirical quantum mechanical (SQM) techniques for the simulation of organic reactions. To enable routine computational study of organic and enzymatic reactions in solution, improved SQM methods are being developed. Inclusion of previously neglected "Pauli" repulsions and the addition of d-orbitals are expected to yield much enhanced results, especially for the description of conformational energy changes and barriers, hydrogen bonding, small ring compounds, and activation energies for reactions. The new SQM methods are being applied in QM/MM calculations to numerous organic reactions in solution, which exhibit significant solvent effects on their rates. This includes nucleophilic substitution, acylation, and Menshutkin reactions, decarboxylations, and [2,3] sigmatropic rearrangements. For general studies of reactions, it is also necessary to incorporate configuration interaction (CI) into the QM framework. This is being pursued using the Pair Excited CI method with initial applications to solvolysis reactions and Bergman cyclization. In all cases, the SQM and CI calculations are performed on-the-fly in MC simulations for the reactions in solution. The recently developed CRA (concerted rotation with variable bond angles) method will be used in MC simulations to perform ab initio folding of polypeptides. Optimization of the simulation protocols and application to small proteins are priority items in this case. Related studies are aimed at the prediction and optimization of the structures of peptides that catalyze asymmetric reactions, e.g., reactions for which the rate is different for mirror-image substrates. The work is expected to have a broad impact on the conceptual understanding of organic reaction mechanisms.