Development and application of ab initio QM/MM methods for mechanistic simulation of reactions in solution and in enzymes

Abstract

Determining the free energies and mechanisms of chemical reactions in solution and enzymes is a major challenge. For such complex reaction processes, combined quantum mechanics/molecular mechanics (QM/MM) method is the most effective simulation method to provide an accurate and efficient theoretical description of the molecular system. The computational costs of ab initio QM methods, however, have limited the application of ab initio QM/MM methods. Recent advances in ab initio QM/MM methods allowed the accurate simulation of the free energies for reactions in solution and in enzymes and thus paved the way for broader application of the ab initio QM/MM methods. We review here the theoretical developments and applications of the ab initio QM/MM methods, focusing on the determination of reaction path and the free energies of the reaction processes in solution and enzymes.

Conical intersections in solution: Formulation, algorithm, and implementation with combined quantum mechanics/molecular mechanics method

“…42,44,62,68,71,72 In such scheme, the QM/MM electrostatic interaction at electronic state I can be expressed as…”

“…This combined QM/MM method allows reliable electronic-structure calculations for chemical reactions, with a realistic and atomistic description of macromolecular or solvent environments. 41,42,47,49,50,62 Such a method takes advantage of the accuracy of the QM methods for chemical reactions and the computational efficiency of the MM methods for macromolecular or solvent environments, which normally consist of many thousands of atoms. The development of the QM/MM method has enabled simulations of complex chemical and biological processes, leading to significant advances in our understanding of chemical reaction mechanisms in solution or macromolecules.…”

“…The QM optimization and the MM sampling are sequentially performed until convergence. 42,62,68,70,72,73 This improvement obviates the QM/MM-FE requirement of defining a minimum energy reaction path prior to free energy calculations. 65,66,68,69 Recently, conical intersections of potential energy surfaces for reactions in solution or macromolecules have received much attention.…”

Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs

“…The application of QM/MM methods to studies of biological systems has undergone sustained growth over the past two or more decades. [2][3][4][5][6][7] Although the approach has achieved great success in numerous applications, 8,9 several problems remain to be addressed. One such problem involves the interface between the QM and MM subsystems.…”

“…One such problem involves the interface between the QM and MM subsystems. Proper description of the junction between the two subsystems has been widely studied, [8][9][10][11][12][13] and several approaches a) Author to whom correspondence should be addressed. Electronic mail:…”