Molecular mechanics calculation of geometries of NAD+ derivatives, modified in the nicotinamide group, in a ternary complex with horse liver alcohol dehydrogenase.

This study examines the structure of seven variations of NAD+, a coenzyme necessary for cellular function, as they interact with a specific enzyme in horse liver. Using molecular mechanics, the study seeks to understand how modifications in a part of the NAD+ molecule impact these interactions and relate to its reactivity.

Research Methodology

• The researchers focussed on how the nicotinamide group, a component of NAD+, interacts with horse liver alcohol dehydrogenase (LADH).
• They used a technique known as Molecular Mechanics Energy Minimization, facilitated by the AMBER software to predict more stable structures of the molecules.
• Initial models used in these calculations were based on X-ray crystallographic data previously reported by other researchers. Specifically, the geometry of the NAD+/Me2SO/LADH complex was used as a starting point for this study.

Study Details

• For the study, seven different NAD+ analogues were created, all with alterations in their nicotinamide group. These NAD+ variations were then observed to interact with the components of the LADH enzyme within a range of 0.6 nanometers from their initial position.
• The molecular interactions observed were between NAD+ analogues, the enzyme (LADH), dimethyl sulfoxide (Me2SO), and zinc ions (Zn2+).

Significance of Results

• The calculations made during the study were able to rationalize individual effects caused by changes in the NAD+ molecules and evaluate essential interactions with the enzyme, Me2SO, and Zn2+ without need for additional X-ray data.
• The study demonstrated that reactivity of NAD+ derivatives can be qualitatively related to the position of the pyridine part (another component of NAD+) in the active site of the enzyme, indicating that variations in NAD+ structure have significant impacts on reactivity.