pKa calculations in solution and proteins with QM/MM free energy perturbation simulations: A quantitative test of QM/MM protocols

Content Provider	CiteSeerX
Author	Riccardi, Demian Schaefer, Patricia Cui, Qiang
Abstract	The accuracy of biological simulations depends, in large part, on the treatment of electrostatics. Due to the availability of accurate experimental values, calculation of pKa provides stringent evaluation of computational methods. The generalized solvent boundary potential (GSBP) and Ewald summation electrostatic treatments were recently implemented for combined quantum mechanical and molecular mechanics (QM/MM) simulations by our group. These approaches were tested by calculating pKa shifts due to differences in electronic structure and electrostatic environment; the shifts were determined for a series of small molecules in solution, using various electrostatic treatments, and two residues (His 31, Lys 102) in the M102K T4-lysozyme mutant with large pKa shifts, using the GSBP approach. The calculations utilized a free energy perturbation scheme with the QM/MM potential function involving the self-consistent charge density functional tight binding (SCC-DFTB) and CHARMM as the QM and MM methods, respectively. The study of small molecules demonstrated that inconsistent electrostatic models produced results that were difficult to correct in a robust manner; by contrast, extended electrostatics, GSBP, and Ewald simulations produced consistent results once a bulk solvation contribution was carefully chosen. In addition to the electrostatic treatment, the pKa shifts were also sensitive to the level of the QM method and the scheme of treating QM/MM Coulombic interactions; however, simple perturbative corrections based on SCC-DFTB/CHARMM trajectories and higher level single point energy
File Format	PDF
Journal	J. Phys. Chem. B
Language	English
Access Restriction	Open
Subject Keyword	Qm Mm Protocol Quantitative Test Pka Calculation Small Molecule Pka Shift Qm Mm Generalized Solvent Boundary Potential Qm Mm Coulombic Interaction Large Part Simple Perturbative Correction Electronic Structure Consistent Result Electrostatic Treatment Computational Method Mm Method Electrostatic Environment Inconsistent Electrostatic Model Ewald Summation Electrostatic Treatment Large Pka Shift M102k T4-lysozyme Mutant Scc-dftb Charmm Trajectory Free Energy Perturbation Scheme Qm Method Stringent Evaluation Various Electrostatic Treatment Qm Mm Potential Function Level Single Point Energy Robust Manner Accurate Experimental Value Bulk Solvation Contribution Gsbp Approach Molecular Mechanic Biological Simulation Ewald Simulation
Content Type	Text
Resource Type	Article