Combining Evolutionary Conservation and Quantum Topological Analyses To Determine Quantum Mechanics Subsystems for Biomolecular Quantum Mechanics/Molecular Mechanics Simulations

Abstract

Selection of residues and other molecular fragments for inclusion in the quantum mechanics (QM) region for QM/ molecular mechanics (MM) simulations is an important step for these calculations. Here, we present an approach that combines protein sequence/structure evolution and electron localization function (ELF) analyses. The combination of these two analyses allows the determination of whether a residue needs to be included in the QM subsystem or can be represented by the MM environment. We have applied this approach on two systems previously investigated by QM/MM simulations, 4-oxalocrotonate tautomerase (4OT) and ten-eleven translocation-2 (TET2), that provide examples where fragments may or may not need to be included in the QM subsystem. Subsequently, we present the use of this approach to determine the appropriate QM subsystem to calculate the minimum energy path (MEP) for the reaction catalyzed by human DNA polymerase λ (Polλ) with a third cation in the active site. Our results suggest that the combination of protein evolutionary and ELF analyses provides insights into residue/ molecular fragment selection for QM/MM simulations.

Influence of the Greater Protein Environment on the Electrostatic Potential in Metalloenzyme Active Sites: The Case of Formate Dehydrogenase

“…Fluctuations that mandate efficient sampling, for example, in the electrostatic potential (ESP), are increasingly recognized as playing important roles in enzyme action. − Moreover, it is essential to treat the active site and surrounding key residues with QM to quantify bond rearrangement, polarization, and charge transfer. − Although small QM regions may produce a reasonable prediction of a reaction mechanism, the treatment of a large number of residues with QM may be necessary to describe charge transfer between the core active site and the surrounding protein environment. Similarly, a large QM region size ensures the inclusion of all residues that are important for enzyme action. − Regarding the challenges for QM region selection, systematic approaches can provide unbiased insights into the electronic environment of the enzyme and the detection of crucial residues to improve the accuracy of the QM/MM. − …”

Universal QM/MM Approaches for General Nanoscale Applications

“…[189] Many approaches have emerged to more systematically decide which subentities of a nanoscopic system should be included in the QM region. [67,[190][191][192] For instance, Kulik and coworkers [190] introduced the charge shift analysis (CSA) and the Fukui shift analysis (FSA) approaches. Changes in either the partial charges or the condensed Fukui functions of specific residues are evaluated as a response to modifications of the QM region.…”

Computational Investigations of Selected Enzymes From Two Iron and α-ketoglutarate-Dependent Families

“…[104,106,109] Similar to the second-shell water for the ferryl intermediate in the AlkB family enzymes mentioned above, this water plays an important structural and electronic role. [41,104,106,109] In the work performed by Lu et al, the reaction begins with the formation of the peroxy bridge. This causes the hydroxyl group of 5hmC to be in close enough proximity to interact with R1261 and the peroxy moiety.…”

“…Several methods currently suggested in the literature for building the QM region include protein sequencing and structural evolution analyses, electron localization function or charge shift analysis. [41,42] Once the regions have been determined, the boundary between the two must be specially handled, especially if there are bonds that are "cut" across the QM/MM boundary. There are a variety of methods used throughout the literature to address this issue including the pseudobond approach, link atoms and frozen localized orbitals.…”