Molecular Modeling and Interaction Analysis of Cannabinoid Receptor Interacting Protein CRIP1b

Abstract

The Human Cannabinoid receptor interacting protein (CRIP1b), a novel protein, is encoded by Cnrip gene loacted on chromosome number 2. CRIP1b is involved in modulation of CB1 cannabinoid receptor's cellular localization and signal transduction but its structure and function remains uncharacterized. The present study has been aimed at investigating three dimensional structure in an effort to provide clues to CRIP1b function. An ab initio modeling approach for prediction of CRIP1a structure has been applied since CRIP1b protein does not share any significant sequence homology to other proteins. The best model obtained from modelling studies for CRIP1b has a compact structure of beta sheets along with a small helix and loops, which is supported by zDOPE score, secondary structure data, Ramachandram plot, and other validation methods. Since CRIP1b protein interacts with the last nine amino acids of the C-terminus of the human CB1 Cannabinoid receptor, the interactions between CRIP1b and a CB1 distal C-terminus nine-mer peptide were studied by performing molecular docking. The best model obtained was docked with CB1 C-terminal peptide, followed by molecular dynamics simulations to investigate binding and relative stability between CB1 and CRIP1a. Molecular docking revealed the involvements of a few hydrogen bonds in binding pocket of CRIP1b. Further the entire complex was optimized by 20 ns MD simulation with Gromacs4.5.5 and the rearrangements of hydrogen bonds leading to structural changes. The relationship between Cannabinoid receptor isoform one (CB1) and CRIP1b have potential to play significant roles in pain management, addiction, cardiovascular diseases, diabetes, and neurodegenerative disorders.