A semiempirical method optimized for modeling proteins

Abstract

Context In recent years, semiempirical methods such as PM6, PM6-D3H4, and PM7 have been increasingly used for modeling proteins, in particular enzymes. These methods were designed for more general use, and consequently were not optimized for studying proteins. Because of this, various specific errors have been found that could potentially cast doubt on the validity of these methods for modeling phenomena of biochemical interest such as enzyme catalytic mechanisms and protein-ligand interactions. To correct these and other errors, a new method specifically designed for use in organic and biochemical modeling has been developed. Methods Two alterations were made to the procedures used in developing the earlier PMx methods. A minor change was made to the theoretical framework, which affected only the non-quantum theory interatomic interaction function, while the major change involved changing the training set for optimizing parameters, moving the focus to systems of biochemical significance. This involved both the selection of reference data and the weighting factors, i.e., the relative importance that the various data were given. As a result of this change of focus, the accuracy in prediction of heats of formation, hydrogen bonding, and geometric quantities relating to non-covalent interactions in proteins was improved significantly.

Evaluation of the electronic density at critical points of hydrogen bonds: PM7 a good alternative to ab‐initio methods

“…In the latter case, the results are comparable with the coupled cluster (CCSD(T) [40]), reference method in the context of electronic structure [38]. Similarly, use of PM7 model for hydrogen bonding has been done by several groups in recent times [41–44].…”

Do electrostatic interactions make a difference in physics‐based AutoDock4 scoring function?

“…As an additional method, we used PM7‐COSMO charge model which explicitly accounts for solvation effects. PM7 is a semi‐empirical method based on Neglect of Diatomic Differential Overlap (NDDO) approximation which was parameterized to reproduce high‐level ab initio reference data (such as CCSD(T)/CBS intermolecular interaction energies) and various experimental quantities (such as enthalpies of formation) 50,51 . Solvation effects were accounted for by using an implicit COSMO solvation model.…”

The Peptide Bond: Resonance Increases Bond Order and Complicates Fragmentation

“…The coupling between the lone pair of N and π(CO) orbitals is of major relevance to partial and approximate methods, in particular, fragmentation methods where a fragment boundary separates these two orbitals in two different fragments. Also, there is some relevance to force fields modeling the peptide bond [44,45] and their interface with QM. [46,47,48] Now, armed with an understanding of the peptide bond, a solution to the fragmentation problem in FMO is proposed.…”