Theories Of Enzyme Catalysis Research Articles

The Gibbs Energy–Potential Energy Conundrum and Chemical Reactivity: Implications for Catalysis and Enzyme Action

The interpretation of transition state theory via reaction energy profiles is problematical, as it remains unclear whether the energy being represented is the Gibbs energy or the potential energy. Although transition state theory is formally an extension of classical equilibrium theory, employing the Gibbs energy can lead to ambiguities in explaining reactivity trends and differences. Thus, the differential reactivity of the carbonyl group in carboxylic esters and carboxylic acid chlorides, when present in the same molecule, can only be explained by invoking transition state effects because of the common ground state. The said transition state effects, however, apparently need implausible assumptions.
 It is argued herein that these ambiguities can be avoided by employing potential energy. In particular, by invoking the “localized” potential energy at a reactive center, ground state effects can be brought into play. This is likely to be largely vibrational potential energy, as this is closely involved in bond breaking and making. It appears, therefore, that transition state theory is best viewed in a qualitative sense for it to be practically meaningful.
 These arguments, in fact, have intriguing implications for catalysis, particularly the theory of enzyme catalysis. Thus, enzymes apparently possess large negative Gibbs energies of formation, hence their reactivity cannot be explained by ground state effects. However, if the “localized” potential energy of the reactive groups in the active site is considered, the phenomenal reactivity of enzymes becomes comprehensible, in an alternative to the Pauling hypothesis of transition state stabilization. This generally implies that the action of catalysts needs to take into account the ground state potential energy of the catalyst, which is almost always ignored in current theoretical treatments.

A Process Theory of Enzyme Catalytic Power – the Interplay of Science and Metaphysics

Enzymes are protein catalysts of extraordinary efficiency, capable of bringing about rate enhancements of their biochemical reactions that can approach factors of 1020. Theories of enzyme catalysis, which seek to explain the means by which enzymes effect catalytic transformation of the substrate molecules on which they work, have evolved over the past century from the “lock-and-key” model proposed by Emil Fischer in 1894 to models that explicitly rely on transition state theory to the most recent theories that strive to provide accounts that stress the essential role of protein dynamics. In this paper, I attempt to construct a metaphysical framework within which these new models of enzyme catalysis can be developed. This framework is constructed from key doctrines of process thought, which gives ontologic priority to becoming over being, as well as tenets of a process philosophy of chemistry, which stresses environmentally responsive molecular transformation. Enzyme catalysis can now be seen not as enzyme acting on its substrate, but rather as enzyme and substrate entering into a relation which allows them to traverse the reaction coordinate as an ontologic unity.

Transition structures in vacuo and the theory of enzyme catalysis. Rubisco's catalytic mechanism: a paradigmatic case?

The molecular mechanism of Rubisco is discussed from the theoretical perspective provided by saddle points of index 1 (SPi-1) for the enolization, carboxylation and oxygenation of Rubisco's substrate, d-ribulose-1,5-bisphosphate, by using 3,4-dihydroxy-2-pentanone as substrate model and ab initio SCF MO at a 3-21G basis set level of theory. Intramolecular hydrogen transfer is shown to be a possible pathway for enolization. The geometric conformation of the in vacuo carboxylation transition structure is found to be superimposable on the transition state analogue bound to Rubisco. For oxygenation, the lowest energy SPi-1 has a triplet spin electronic structure and the carbon fragment has a large structural overlap with the C-fragment of the enolization and carboxylation SPi-1 structures. An explanation for the bifunctionality of the Rubisco enzyme arises from these structural similarities: once the catalytic process begins and the transition structure for the enolization step is reached, the system can catalyse both the carboxylation and the oxygenation processes with very little structural changes of the substrate moiety. Thus, depending on the gas molecule that enters into the active site, CO2 or O2, Rubisco will catalyse carboxilation or oxygenation of the substrate, respectively. The “inevitability” hypothesis for the oxygenation reaction is given theoretical support.

Transition structures in vacuo and the theory of enzyme catalysis. Rubisco's catalytic mechanism: a paradigmatic case?

The molecular mechanism of Rubisco is discussed from the theoretical perspective provided by saddle points of index 1 (SPi-1) for the enolization, carboxylation and oxygenation of Rubisco's substrate, d-ribulose-1,5-bisphosphate, by using 3,4-dihydroxy-2-pentanone as substrate model and ab initio SCF MO at a 3-21G basis set level of theory. Intramolecular hydrogen transfer is shown to be a possible pathway for enolization. The geometric conformation of the in vacuo carboxylation transition structure is found to be superimposable on the transition state analogue bound to Rubisco. For oxygenation, the lowest energy SPi-1 has a triplet spin electronic structure and the carbon fragment has a large structural overlap with the C-fragment of the enolization and carboxylation SPi-1 structures. An explanation for the bifunctionality of the Rubisco enzyme arises from these structural similarities: once the catalytic process begins and the transition structure for the enolization step is reached, the system can catalyse both the carboxylation and the oxygenation processes with very little structural changes of the substrate moiety. Thus, depending on the gas molecule that enters into the active site, CO 2 or O 2, Rubisco will catalyse carboxilation or oxygenation of the substrate, respectively. The “inevitability” hypothesis for the oxygenation reaction is given theoretical support.

Computer assisted simulations and molecular graphics methods in molecular design. 1. Theory and applications to enzyme active-site directed drug design

A survey is presented of model building techniques, computer-assisted molecular dynamics simulations and a new theory of enzyme catalysis. Some aspects of the theoretical formalism are given. Enzyme active-site directed drug design is illustrated with examples taken from molecular modeling studies using FAD-containing disulphide oxidoreductases, proteinases and carbonic anhydrases.

A Shifting Specificity Model for Enzyme Catalysis

A new model for general enzyme catalysis challenges the idea that transition state complementarity of enzyme active sites to the reactions they catalyze is the sole source of their catalytic efficacy. The "shifting specificity" model rejects the widely held view that strong interactions of the enzyme with substrate inhibit catalytic efficiency and previously published data are presented which show that a strong interaction of substrate with the enzyme active site actually facilitates its conversion to product. Furthermore, this new model defines a role for the entire enzyme molecule unlike most theories of enzyme catalysis which are concerned only with the interaction of the active site with substrate. This shifting specificity model for general enzyme catalysis may be expressed succinctly as: (i) enzymes have evolved to bind substrates; (ii) enzyme/substrate complexes have evolved to bind transition states; (iii) a stronger interaction of substrate with the enzyme facilitates a more rapid conversion to product. This last effect results from a more efficient modulation of the global enzyme conformation by tight-binding substrates. It is suggested that the addition of atomic mass to the enzyme, which interacts with the enzyme in the same manner in which the enzyme domains interact with one another, must alter the low-frequency, global vibrations of the enzyme to produce a different overall conformation. Nature has selected for that conformational change which shifts the active site complementarity from substrate-specific to transition state-specific. Thus, this model suggests a means for an efficient realization of the substrate-binding energy in the transition state of the reaction. General aspects of this model are discussed in light of the current view of enzyme catalysis.

Unstable electron pairing and the energy loan model of enzyme catalysis

A theory of enzyme catalysis is described which utilizes a thermodynamically consistent construction of a free energy diagram with different pathways for complex formation and decomposition. The switch to the decomposition pathway occurs when downward uncertainty and thermal fluctuations make possible a short-lived potential energy dominance in which parallel spin electrons are paired and thus free to drop below the energy floor normally maintained by the Pauli exclusion principle. Such pairing is possible if van der Waal's and other weak interactions holding the complex together impose confinement constraints on parallel spin electrons, thereby both increasing uncertainty fluctuations in their kinetic energy and weakly favoring a phase correlation in their motion (which can be interpreted in terms of an exchange of virtual particles). The paired configuration is highly unstable and thus energy released by pair falling is either immediately recaptured to re-establish a normal orbital structure or, if the pair persists long enough to produce a nuclear motion, recaptured at the end of this motion. In the latter case the release of energy can be thought of as an energy loan which finances the switch to the lower activation energy pathway without compromising an energy-balanced regeneration of the enzyme. The advantage is that the complex (because of its instability) has a real free energy which is lower than the free energy which would be assigned to it on the basis of its equilibrium concentration. This increases the specificity and speed of complex formation without decreasing the speed of decomposition. The theory predicts that the magnetic moment which marks the pair should accompany the nuclear (e.g. allosteric) motion and that the pair formation stage of the enzymatic process should have an anomalous temperature dependence. Variations of the model may be constructed to deal with a number of processes involving macromolecular motions, including sequential processes in catalysis, allosteric control, persistent molecular motions, self-assembly, energy transfer, channeled transport, and protection against inhibitors.