Binding site prediction between lysozyme and glucose-regulated protein 78, a hope to fight amyloidosis

Abstract

Amyloidosis is an extraordinarily vigorous and heterogeneous group of disorders that causes numerous organ failures due to the precipitation of misfolded proteins. Many of these damaged proteins are discarded before causing any fatal diseases due to the contribution of the protein quality control (PQC) system and its chaperons, including glucose-regulated protein (GRP78). One of the most important enzymatic proteins inside the body is lysozyme, which is reported to have many mutated variants that may cause amyloid fibrils. This study used structural bioinformatics and molecular dynamics simulations to test and suggest binding sites for the human lysozyme protein with GRP78. Multiple sequence alignment (MSA) shows that part of the lysozyme envelope protein (C65–C81 cyclic region) has high similarities (30.77% identity) with the cyclic Pep42. Additionally, the binding between the lysozyme cyclic region (C65–C81) and GRP78 substrate binding domain (SBD) is found favorable. The number and types of interactions vary between each of the mutant isoforms of lysozyme. The more significant the conformational changes in the mutation, the greater its probability of aggregation and the formation of amyloid fibrils. Each mutation leads to different interactions and binding patterns with GRP78. The present computational study suggests a lysozyme-GRP78 binding site, thus paving the way for drug designers to construct suitable carriers that can collect misfolded lysozyme proteins and eliminate them from the body, preventing their aggregation and amyloidogenesis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Amyloidosis
• GRP78
• lysozyme
• molecular dynamic simulation
• protein–protein docking
• structural bioinformatics

Acknowledgments

MDS was performed on the Bibliotheca Alexandrina supercomputing facility in Alexandria, Egypt. Special thanks to our colleague Ibrahim Mohamad, a teaching assistant at the Biophysics Department, Cairo University, for his great help and effort in this work.

Author contribution

A.A.E. owned the research idea and revised the manuscript. A.M.E. did the calculations and wrote the first draft. W.M.E. revised the final version of the manuscript. All the authors approve the final form of the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors approve of publishing this work.

Disclosure statement

The authors declare that there is no conflict of interest in this work.

Availability of data and materials

Data are available upon reasonable request from authors.