Abstract
Elucidating the origin of enzymatic catalysis stands as one the great challenges of contemporary biochemistry and biophysics. The recent emergence of computational enzymology has enhanced our atomistic-level description of biocatalysis as well the kinetic and thermodynamic properties of their mechanisms. There exists a diversity of computational methods allowing the investigation of specific enzymatic properties. Small or large density functional theory models allow the comparison of a plethora of mechanistic reactive species and divergent catalytic pathways. Molecular docking can model different substrate conformations embedded within enzyme active sites and determine those with optimal binding affinities. Molecular dynamics simulations provide insights into the dynamics and roles of active site components as well as the interactions between substrate and enzymes. Hybrid quantum mechanical/molecular mechanical (QM/MM) can model reactions in active sites while considering steric and electrostatic contributions provided by the surrounding environment. Using previous studies done within our group, on OvoA, EgtB, ThrRS, LuxS and MsrA enzymatic systems, we will review how these methods can be used either independently or cooperatively to get insights into enzymatic catalysis.
Highlights
Enzymes, being essential to life, have long been the focus of considerable efforts, in order to understand their properties and biochemical roles
By a synergetic application of docking, molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/Molecular mechanics (MM)) for each of the possible substrate isomers we investigated the nature of the substrate-bound active site and the possible initial mechanistic reaction steps [17]
This review presented a variety of examples pertaining to the use of distinguished computational methods in deciphering enzyme catalysis
Summary
Enzymes, being essential to life, have long been the focus of considerable efforts, in order to understand their properties and biochemical roles. Various “models” have been developed to explain their machinery: some have focused on the possible role of the overall structure and corresponding conformational variations [8,9,10], while others have focused on the role of a few chemical species and functional groups within their active sites [11,12,13]. This has led to the gradual development of a more holistic picture of enzymatic catalysis. Enzymes are increasingly seen as systems that must be considered both at atomistic and macroscopic levels
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