Folding of Pig Gastric Mucin Non-glycosylated Domains: A Discrete Molecular Dynamics Study

TL;DR

This study uses discrete molecular dynamics to investigate how non-glycosylated domains of gastric mucin fold under different pH conditions, revealing structural changes that are crucial for mucin gelation and stomach protection.

Contribution

It provides the first detailed simulation-based analysis of non-repetitive mucin domains' folding behavior at varying pH levels, highlighting the role of salt bridges and beta-strand formation.

Findings

Salt bridges form at neutral pH, leading to compact structures.

Low pH causes salt bridges to break, resulting in extended conformations.

Simulated beta-strand content agrees with experimental CD data.

Abstract

Mucin glycoprotein consist of tandem repeating glycosylated regions flanked by non-repetitive protein domains with little glycosylation. These non-repetitive domains are involved in the pH dependent gelation of gastric mucin, which is essential to protecting the stomach from autodigestion. We have examined the folding of the non-repetitive sequence of von Willebrand factor vWF-C1 domain (67 amino acids) and PGM 2X (242 amino acids) at neutral and low pH using Discrete Molecular Dynamics. A four-bead protein model with hydrogen bonding and amino acid-specific hydrophobic/hydrophilic and electrostatic interactions of side chains) was used. The simulations reveal that the distant N- and C-terminal regions form salt-bridges at neutral pH giving a relatively compact folded structure. At low pH, the salt bridges break giving a more open and extended structure. The calculated average value of the beta-strand increases from 0.23 at neutral pH to 0.36 at low pH in very good agreement with CD data. Simulations of vWF C1 show 4-6 beta strands separated by turns/loops and we found that pH did not affect significantly the folded structure. The average beta-strand structure of 0.32 was again in very good agreement with the CD results.