Implementation of the Solvent Macromolecule Boundary Potential and Application to Model and Realistic Enzyme Systems

Abstract

The implementation of the solvent macromolecule boundary potential (SMBP) by Benighaus and Thiel (J. Chem. Theory Comput. 2009, 5, 3114) into the program package CHARMM is presented. The SMBP allows for the efficient calculation of solvent effects for large macromolecules using irregularly shaped dielectric boundaries. In contrast to the generalized solvent boundary potential (GSBP) by Roux et al. (J. Chem. Phys. 2001, 114, 2924) from which it is derived, the SMBP is targeted for quantum mechanical/molecular mechanical (QM/MM) setups using ab initio methods for the QM part. After presenting benchmark results for simple model systems, applications of the SMBP for the calculation of geometries, reaction energy barriers, and vibrational frequencies for an alkaline phosphatase (AP) enzyme are discussed. Although the effect of the boundary potential on optimized structures (including the transition state) and vibrational frequencies is relatively small, the energetics of the phosphoryl transfer catalyzed by AP depend significantly on the boundary potential. Finally, to emphasize a unique feature of our implementation, we apply both SMBP and GSBP to the calculation of the energy barrier for a proton transfer reaction in a simple model channel, where the effect of an external transmembrane potential is studied. Due to the dipolar response of the polar environment, the effective charge displacement estimated based on the effect of the membrane potential on the proton transfer energetics deviates from the net charge that passes the membrane.

Stabilization of Different Types of Transition States in a Single Enzyme Active Site: QM/MM Analysis of Enzymes in the Alkaline Phosphatase Superfamily

“…92 The O Ser 102 -P distances in the optimized structures are 3.1 (3.4) Å in M06/MM (SCC-DFTBPR/MM), close to the value of 3.1 Å in the crystal structure. The O2 of the substrate (see Fig.2 for labels) coordinates to one of the zinc ions and O1 with the phenyl group is solvated by water molecules.…”

Advances in molecular quantum chemistry contained in the Q-Chem 4 program package

“…This was closely followed by the parallelisation of these full QM/MM Hessian calculations and extension to the mobile block Hessian formalism, significantly reducing CPU and memory requirements for these intensive calculations [297]. Complementing Q-CHEM/CHARMM support for QM/MM dielectric approaches (see also QM/MM/PCM below), the solvent macromolecule boundary potential method has also been interfaced to Q-CHEM [298,299]. Last, but not least, a user-friendly Web interface that facilitates the graphical set-up of QM/MM calculations (i.e., Q-CHEM/CHARMM) was also developed [300].…”

QM/MM free energy simulations: recent progress and challenges

“…4a, the model describes proton transfer between two small water droplets through a “channel”; the confinement effect of the channel is implemented using a set of restraints available in CHARMM 128 and a set of point dipoles are included to stabilize the excess proton in the low-dielectric region of the model. This type of model was used in our previous studies to explore the definition of order parameters for long-range proton transfers, 129 to understand the impact of boundary potential, including an external membrane potential, 130 on proton transfers, and to compare different parameterizations of DFTB3 for studying the free energy of proton transfers. 54 Here we use the model to illustrate the value of REUS for computing free energy profiles over regular umbrella sampling, and to illustrate the flexibility of choosing CVs in metadynamics simulations for gaining new mechanistic insights.…”