QM/MM Calculations on Proteins

In this chapter, I discuss combined quantum mechanics (QM) and molecular mechanics (MM; QM/MM) calculations for proteins. In QM/MM, a small but interesting part of the protein is treated by accurate QM methods, whereas the remainder is treated by faster MM methods. The prime problems with QM/MM calculations are bonds between the QM and MM systems, the selection of the QM system, and the local-minima problem. The two first problems can be solved by the big-QM approach, including in the QM calculation all groups within 4.5-6. Å of the active site and all buried charges in the protein. The third problem can be solved by calculating free energies. It is important to study QM/MM energy components to ensure that the results are stable and reliable. They can also be used to understand the reaction and the effect of the surroundings, eg, by dividing the catalytic effect into bonded, van der Waals, electrostatic, and geometric components and to deduce which parts of the protein contribute most to the catalysis. It should be ensured that the QM calculations are reliable and converged by extending the basis set to quadruple-zeta quality, including a proper treatment of dispersion, as well as relativistic, zero-point, thermal, and entropy effects, and performing calculations with both pure and hybrid density functional theory methods. If the latter give differing results, calibration with high-level QM methods is needed. Reactions that change the net charge should be avoided. QM/MM calculations can be combined with experimental methods.