QM/MM of P450 BM3
Collection of the various points mentioned. Suggestions, feedback, corrections, additions and comments are most welcome.
General Statements of Interest:
- The study does not carry out any MD simulation in order to obtain a minimum energy path or a potential of mean force. Instead what is presented is an adiabatic scan of the reaction coordinate. What does this imply: in the transition state search and in the optimization of the reactants/products, the system is optimized into the next local minimum. So it is implicitly assumed that the difference in energy is caused only by the difference in energy of the active site part of the enzyme. Still it is possible that the transition state (TS) system is in a different local minimum than the reactant and therefore calculating the energy barrier from these two system is somewhat questionable. In the present case, the reaction is characterized by a simple hydrogen transfer, so maybe it is a safe assumption that the two systems indeed do not differ for parts other than the active site.
- TS search: QSite provides the user with three ways of locating TSs: something similar to CalcFC, something like QST2/3 and a general Newton-Raphson minimization (most likely with some sort of Hessian approximation). It is not clear, which method the authors used to compute the TS.
- This point was brought up by Janus. The "message" of the paper is that the induced fit docking (IFD) procedure provides a reasonable starting structure for the reactant species, as confirmed by the REMD. The paper does not claim to report results which aim at reproducing experimental results for the rate constant.
Considering the Boundaries:
- The method is defined such that part of the solvent molecules (the outer 4Å of solvent) are being kept fixed during the optimization. The question was, if this is fair to do? As I can tell from my own work, it can happen that in going from one point on the reaction coordinate to another, the system finds a new, different local minimum and a significant (unrealistic in the sense of "this would not happen if the modeling was more sophisticated") change in energy is observed. This is somehow related to the first point above.
Open Points / Questions:
- We were briefly discussing the way the optimization is being carried out. Apparently, the MM system is being minimized for every QM step of optimization. So no only when the QM gradient is below the threshold. Was there something more to this other than it just being stated?