Journal article
Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study
Journal of biological physics, v 38(4), pp 681-703
Sep 2012
PMID: 24615227
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mucin glycoproteins consist of tandem-repeating glycosylated regions flanked by non-repetitive protein domains with little glycosylation. These non-repetitive domains are involved in polymerization of mucin and play an important role in the pH-dependent gelation of gastric mucin, which is essential for protecting the stomach from autodigestion. We examine folding of the non-repetitive sequence of PGM-2X (242 amino acids) and the von Willebrand factor vWF-C1 domain (67 amino acids) at neutral and low pH using discrete molecular dynamics (DMD) in an implicit solvent combined with a four-bead peptide model. Using
the same implicit solvent parameters
, folding of both domains is simulated at neutral and low pH. In contrast to vWF-C1, PGM-2X folding is strongly affected by pH as indicated by changes in the contact order, radius of gyration, free-energy landscape, and the secondary structure. Whereas the free-energy landscape of vWF-C1 shows a single minimum at both neutral and low pH, the free-energy landscape of PGM-2X is characterized by multiple minima that are more numerous and shallower at low pH. Detailed structural analysis shows that PGM-2X partially unfolds at low pH. This partial unfolding is facilitated by the C-terminal region GLU236-PRO242, which loses contact with the rest of the domain due to effective “mean-field” repulsion among highly positively charged N- and C-terminal regions. Consequently, at low pH, hydrophobic amino acids are more exposed to the solvent. In vWF-C1, low pH induces some structural changes, including an increased exposure of CYS at position 67, but these changes are small compared to those found in PGM-2X. For PGM-2X, the DMD-derived average β-strand propensity increases from 0.26 ± 0.01 at neutral pH to 0.38 ± 0.01 at low pH. For vWF-C1, the DMD-derived average β-strand propensity is 0.32 ± 0.02 at neutral pH and 0.35 ± 0.02 at low pH. The DMD-derived structural information provides insight into pH-induced changes in the folding of two distinct mucin domains and suggests plausible mechanisms of the aggregation/gelation of mucin.
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Details
- Title
- Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study
- Creators
- Bogdan Barz - Physics Dept., Drexel University, Philadelphia, PA 19104 USABradley S Turner - Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215 USARama Bansil - Physics Dept. and Center for Polymer Studies, Boston University, Boston, MA 02215 USABrigita Urbanc - Physics Dept., Drexel University, Philadelphia, PA 19104 USA
- Publication Details
- Journal of biological physics, v 38(4), pp 681-703
- Publisher
- Springer Netherlands; Dordrecht
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000310193000010
- Scopus ID
- 2-s2.0-84867893683
- Other Identifier
- 991014878083404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biophysics