Protein Dynamics and Enzymatic Catalysis

Abstract

This Perspective presents a review of our work and that of others in the highly controversial topic of the coupling of protein dynamics to reaction in enzymes. We have been involved in studying this topic for many years. Thus, this perspective will naturally present our own views, but it also is designed to present an overview of the variety of viewpoints of this topic, both experimental and theoretical. This is obviously a large and contentious topic.

Investigating the Non-Electrostatic Component of Substrate Positioning Dynamics

“…[12][13][14] Protein dynamics have been widely reported as a factor to mediate catalysis. [15][16][17][18][19][20] Their complexity is attributed to the broad range of time scales over which correlated protein motions can occur. 15,19,[21][22][23][24][25][26][27][28] For example, residue vibrations and collision have been proposed to facilitate transition state (TS) barrier crossing in the sub-picosecond time scale (e.g., lactate dehydrogenase, alcohol dehydrogenase, and purine nucleoside phosphorylase).…”

“…[15][16][17][18][19][20] Their complexity is attributed to the broad range of time scales over which correlated protein motions can occur. 15,19,[21][22][23][24][25][26][27][28] For example, residue vibrations and collision have been proposed to facilitate transition state (TS) barrier crossing in the sub-picosecond time scale (e.g., lactate dehydrogenase, alcohol dehydrogenase, and purine nucleoside phosphorylase). 15,21,22 Residue and loop motions have been proposed to facilitate the positioning of substrates to form reactive conformation (or near-attack conformation 29 ) in the pico-to nanosecond time scale (e.g., dihydrofolate reductase, chitinase, β-lactamase, retro-aldolase, Kemp eliminase, glycoside hydrolase, Cytochrome P450, and soybean lipoxygenase).…”

“…15,19,[21][22][23][24][25][26][27][28] For example, residue vibrations and collision have been proposed to facilitate transition state (TS) barrier crossing in the sub-picosecond time scale (e.g., lactate dehydrogenase, alcohol dehydrogenase, and purine nucleoside phosphorylase). 15,21,22 Residue and loop motions have been proposed to facilitate the positioning of substrates to form reactive conformation (or near-attack conformation 29 ) in the pico-to nanosecond time scale (e.g., dihydrofolate reductase, chitinase, β-lactamase, retro-aldolase, Kemp eliminase, glycoside hydrolase, Cytochrome P450, and soybean lipoxygenase). [25][26][27][28][30][31][32][33][34][35][36][37] Conformational change of loops and domains have been demonstrated to enable substrate binding, solvent shielding, or product releasing in the nanosecond to millisecond time scale (e.g., triosephosphate isomerase and adenylate kinase).…”

Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis

“…In thermodynamic terms, enzymes lower the activation energy for reactants to cross the transition-state energy barrier . Enzymatic rate enhancement can also be defined in terms of protein dynamic conformational searches, local catalytic site motions evolved to find the transition-state geometry with high probability. , An experimental approach to explore femtosecond bond vibrational effects on transition-state formation is the isotopic labeling of enzymes. Enzyme proteins labeled fully or in part with amino acids substituted with 2 H, 13 C, and 15 N replacing the normal isotopes produce isotopically heavy enzymes with mass-altered vibrational modes in all or in labeled parts of their architecture.…”

Substrate Positioning Dynamics Involves a Non-Electrostatic Component to Mediate Catalysis

“…Elucidating the catalytic origin of enzymes, a fundamental question in chemistry, guides the development of engineering strategies to create function-enhancing enzyme variants for chemical synthesis, − waste degradation, − fuel production, − disease diagnosis, and treatment. − Protein dynamics, which ranges over 10 orders of magnitude in timescale, − has been widely reported to mediate catalysis. ,,− For example, residue vibrations and collision have been proposed to facilitate transition state (TS) barrier crossing on the subpicosecond time scale (e.g., lactate dehydrogenase, alcohol dehydrogenase, and purine nucleoside phosphorylase). − Residue and loop motions have been proposed to facilitate the positioning of substrates to form a reactive conformation (or near-attack conformation) on the pico- to nanosecond time scale (e.g., dihydrofolate reductase, chitinase, β-lactamase, retro-aldolase, Kemp eliminase, glycoside hydrolase, cytochrome P450, and soybean lipoxygenase). − ,− Conformational changes in loops and domains have been demonstrated to enable substrate binding, solvent shielding, or product release on the nanosecond to millisecond time scale (e.g., triosephosphate isomerase and adenylate kinase). ,,, …”