Fragment molecular orbital study of the cAMP-dependent protein kinase catalyzed phosphoryl transfer: a comparison with the differential transition state stabilization method

Abstract

The importance of key residues to the activity of the cAMP-dependent protein kinase catalyzed phosphoryl transfer and to the stabilization of the transition state of the reaction has been investigated by means of the fragment molecular orbital (FMO) method. To evaluate the accuracy of the method and its capability of fragmenting covalent bonds, we have compared stabilization energies due to the interactions between individual residues and the reaction center to results obtained with the differential transition state stabilization method (Szarek, et al., J. Phys. Chem. B, 2008, 112, 11819-11826) and observe, despite a size difference in the fragment describing the reaction center, near-quantitative agreement. We have also computed deletion energies to investigate the effect of virtual deletion of key residues on the activation energy. These results are consistent with the stabilization energies and yield additional information as they clearly capture the effect of secondary interactions, i.e. interactions in the second coordination layer of the reaction center. We find that using FMO to calculate deletion energies is a powerful and time efficient approach to analyze the importance of key residues to the activity of an enzyme catalyzed reaction.

Three‐body expansion of the fragment molecular orbital method combined with density‐functional tight‐binding

“…So far, FMO2, FMO3, and FMO4 methods have been developed. FMO has been applied to a number of systems …”

“…FMO has been applied to a number of systems. [35][36][37][38] Density-functional tight-binding (DFTB) [39][40][41][42] is a fast parametrized QM method with the Hamiltonian constructed using tabulated parameters, most of which are fit to density functional theory (DFT). DFTB is based on a Taylor series of the density, and the series can be truncated at the power m terms, resulting in DFTBm methods, m 5 1, 2, and 3.…”

Mapping Interaction Energies in Chorismate Mutase with the Fragment Molecular Orbital Method

“…Although tremendous effort − has gone into making the FMO method applicable to optimizing geometries − and transition states, , the FMO method has historically been applied as an energy-refinement method ,, in ligand binding studies, − reaction barrier estimation, or identification of key residues through inspection of the interaction energies between substrates and surrounding residues. , Although the FMO method is significantly more capable and efficient than performing a full QM calculation on a large molecular system, , accurate mapping of catalytic reactions in many cases requires the inclusion of the environment (solvent, ions, etc.). To provide an even more efficient method to map complete reactions, the effective fragment molecular orbital − (EFMO) method was devised.…”

Efficient Geometry Optimization of Large Molecular Systems in Solution Using the Fragment Molecular Orbital Method

“…The fragment molecular orbital (FMO) method − is a fragmentation approach, in which each fragment is calculated in the presence of the electrostatic potential (ESP) exerted by the rest of the fragments, followed by calculations of fragment pairs. FMO has been applied to many large systems. − FMO has been combined with PCM for energy and gradient − and other solvation models. − Geometry optimizations have been done with FMO using hybrid , approaches and full QM for small proteins and inorganic nano rings . Alternatively, one can use various partial geometry optimization schemes, , which benefit from fragmentation making calculations effective and accurate.…”