Molecular Dynamics Simulation of Human Pancreatic Lipase and Lipase-colipase Complex: Insight into the Structural Fluctuations and Conformational Changes

Sikiru Akinyeye Ahmed,Zaheer-Ul Haq Qasmi,Nizakat Ali,Ruqaiya Khalil,Urooj Qureshi

doi:10.11648/j.ijctc.20200801.13

Sikiru Akinyeye Ahmed, Zaheer-Ul Haq Qasmi + Show 3 more

Open Access

https://doi.org/10.11648/j.ijctc.20200801.13

Copy DOI

Abstract

Although the structure of Human Pancreatic Lipase has been documented through the X-ray crystallography, the knowledge about the molecular rearrangement and dynamic equilibrium in the structure (particularly in the catalytic triad and lid domains) is very scanty. The structural fluctuations and conformational changes undergo by Human Pancreatic Lipase (HPL) with and without colipase were computationally investigated through molecular dynamics simulation technique using GROMACS 2018.4, MOE 2016.0801 and VMD softwares in order to gain insight into the complex transitions at different domains. The structural stability was revealed vis-a-vis Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuations (RMSF) plots. The levels of compactness/folding and conformational changes of the protein were determined using Radius of gyration and secondary analysis respectively. Salt bridge analysis gives more ionic pairs interactions than experimentally determined results. Results show that though both proteins are stable, lipase-colipase complex is more deviated and flexible than lipase. Also, additional information regarding the conformational transitions, interactions and dynamics that govern stability of lipase-colipase complex which were ‘hidden’ to experimental techniques were revealed.

Highlights

Human Pancreatic lipase is one of the key enzymes in the hydrolysis of triglycerides into monoglycerides and free fatty acid, and is considered a promising target for the treatment of obesity [1]
Human pancreatic lipase is a glycoprotein containing 449 amino acid residues [2, 3] and it consists of two distinct domains; a large Nterminal domain comprising the active site, and a smaller C-terminal domain having a β-sandwich fold that forms the main binding sites for the colipase [2, 4,5,6]
By employing molecular dynamics simulations, the present study has revealed information beyond what is available in the static structures deposited in the Protein Data Bank

Summary

Introduction

Human Pancreatic lipase is one of the key enzymes in the hydrolysis of triglycerides into monoglycerides and free fatty acid, and is considered a promising target for the treatment of obesity [1]. Human pancreatic lipase is a glycoprotein containing 449 amino acid residues [2, 3] and it consists of two distinct domains; a large Nterminal domain (residue 1-336) comprising the active site (hydrophobic), and a smaller C-terminal domain (residues 337-449) having a β-sandwich fold that forms the main binding sites for the colipase [2, 4,5,6]. The activated form is shorter than the procolipase from which five amino acids have been removed by trypsin [3]. This pentapeptide is called enterostatin and it is believed to play a role in satiety regulation and fat intake [8]

Methods

Results

Conclusion