The Promoting Vibration in Human Heart Lactate Dehydrogenase Is a Preferred Vibrational Channel

Abstract

We examine if the rate promoting vibration of lactate dehydrogenase is a preferred axis of thermal energy transfer. While it seems plausible that such a mechanistically important motion is also a favored direction of energy transfer, none of the previous studies of rate promoting vibrations in enzymatic catalysis have addressed this question. It is equally likely that the promoting vibration, though catalytically important, has no different properties than any other axis in the protein. Resolution of this issue is important for two reasons: First, if energy is transferred along this axis in a preferred fashion, it shows that the protein is engineered in a way that transfers thermal energy into a motion that is coupled to the chemical step. Second, the discovery of a preferred direction of thermal transfer provides a potential route to experimental verification of the promoting vibration concept. Our computational experiments are specifically designed to mimic potential laser experiment with the deposition of thermal energy in an active site chromophore with subsequent measurement of temperature at various points in the protein. Our results indicate that the promoting vibration is indeed a preferred channel of energy transfer. In addition, we study the vibrational structure of the protein via the dynamical structure factor to show preferred vibrational motion along the promoting vibration axis is an inherent property of the protein structure via thermal fluctuations.

Engineered control of enzyme structural dynamics and function

“…Similar findings have been found in other enzymes, especially those in which quantum tunneling may play a role . Quantum tunneling behavior is often probed using kinetic isotope effects (KIEs) (see reviews).…”

Reaction mechanism and reaction coordinates from the viewpoint of energy flow

“…25,26 A very interesting suggestion is that promoting vibrations, 27,28 which are important reaction coordinates for some enzymatic reactions, are preferred channels of heat dissipation in lactate dehydrogenase. 29 However, to date there has been no study on energy flows during an activated transition process to our knowledge.…”

The enzymatic reaction catalyzed by lactate dehydrogenase exhibits one dominant reaction path

“…In order to achieve a reactive enzyme-substrate complex, we protonated the active site histidine (His193) and substituted the oxamate nitrogen with a carbon to create the pyruvate ligand. We generated the parameters for the pyruvate ligand previously [28]. We solvated each system with TIP3P explicit water models [29] and neutralized the charged ternary complex with potassium ions to ensure physiological relevance.…”