Structural and energetic insights into the interaction of niacin with GPR109A receptor

Authors: ADEPU, KIRAN KUMAR - Arkansas Children'S Nutrition Research Center (ACNC); KACHHAP, SANGITA - Polish Academy Of Sciences; ANISHKIN, ANDRIY - University Of Maryland; CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Bioinformatics and Biology Insights
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2021
Publication Date: 11/27/2021
Citation: Adepu, K., Kachhap, S., Anishkin, A., Chintapalli, S.V. 2021. Structural and energetic insights into the interaction of niacin with GPR109A receptor. Bioinformatics and Biology Insights. https://doi.org/10.1177/11779322211056122.
DOI: https://doi.org/10.1177/11779322211056122

Interpretive Summary: Niacin also known as vitamin B3 or nicotinic acid is an important nutrient in the body for general good health. It is mainly used as a supplement which helps in lowering cholesterol, ease arthritis and boost brain function among other benefits. However, higher doses of niacin pose risks such as liver damage, gastrointestinal problems or glucose tolerance. G-protein coupled receptor GPR109A, a transmembrane protein mediates the antilipolytic effect of niacin. Thus, it is important to understand niacin-GPR109A structural interactions. Experimental evidence suggested that the ARG111 and ARG251 plays a critical role in binding niacin. To further understand how niacin interacts with GPR109A, we conducted computer modeling studies to elucidate the GPR109A structure and the interaction site for niacin. Studies also included to calculate the entry region of niacin into the protein apart from binding site residues. Based on our observations from five different independent computer models using molecular dynamic simulations, and a negative control of GPR109B which does not bind to niacin, our results are in accordance with the published experimental/mutational studies. Computational structural analysis reveals the importance of critical basic residues in the crevice, which along with other hydrophobic residues in binding and residues N86, S178 and S179 may play a significant role in the entry mechanism of niacin.

Technical Abstract: The transmembrane G-protein coupled receptor GPR109A has been previously shown to function as a receptor for niacin in mediating antilipolytic effects. Although administration of high doses of niacin have shown beneficial effects on lipid metabolism, however, it is often accompanied by disturbing side effects such as flushing, liver damage, glucose intolerance, or gastrointestinal problems. Thus, it is important to understand niacin-GPR109A interactions, which can be beneficial for the development of alternate drugs having antilipolytic effects with less or no side effects. To get into the structural insights on niacin binding to GPR109A, we have performed 100 nanoseconds long all-atom MD simulations of five niacin-GPR109A complexes (automatically docked pose0, and randomly placed niacin in poses 1 to 4 in the receptor crevice) and analyzed using binding free energy calculations and H-bond analysis. Steered MD simulations was used to get an average force for niacin translocation between the bulk and the external crevice of the wild type and mutant (N86Y, W91S, S178I, and triple mutant of all three residues) GPR109A receptors, as well as GPR109B (as a control that does not bind niacin). The H-bond analysis revealed that TMH3 residue R111 interacts with niacin in a total of 4 (poses 0 to 3) complexes, while residues C177, S178, and S179 contact niacin in complex pose-4, and all these complexes were energetically stable. According to steered MD simulations, all the GPR109A mutants and GPR109B required greater force than that of wild type GPR109A to translocate in the external crevice, suggesting increased sterical obstacles. Thus, the residues N86 (at the junction of TMH2/ECL2), W91 (ECL2), R111 (TMH3), and ECL3 residues: C177, S178, S179 play an important role for optimal routing of niacin entry and to bind GPR109A.