Alport Syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties

Maya Srinivasan, Sebastien G M Uzel, Alfonso Gautieri, Sinan Keten, Markus J. Buehler*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Alport Syndrome is a genetic disease characterized by breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level structure-property relationships of this disease using a bottom-up computational materiomics approach implemented through large-scale molecular dynamics simulation. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of single-residue glycine substitution mutations of varying clinical severity are studied in short segments of type IV tropocollagen molecules. The segments with physiological amino acid sequences are equilibrated and then subjected to tensile loading. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration (with the kink located at the mutation site) and a significant alteration of the molecules' stress-strain responses and stiffnesses. These results suggest that localized structural changes at amino acid level induce severe alterations of the molecular properties. Our study opens a new approach in pursuing a bottom-up multi-scale analysis of this disease.

Original languageEnglish (US)
Pages (from-to)503-510
Number of pages8
JournalJournal of Structural Biology
Volume168
Issue number3
DOIs
StatePublished - Dec 1 2009

Keywords

  • Alport Syndrome
  • Breakdown
  • Computational biology
  • Defects
  • Elasticity
  • Failure
  • Flaws
  • Genetic disease
  • Materiomics
  • Mechanical property
  • Nanomechanics
  • Protein material

ASJC Scopus subject areas

  • Structural Biology

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