Linking genetics and mechanics in structural protein materials: A case study of an Alport syndrome mutation in tropocollagen

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Many proteins found in biological systems provide functional properties through the formation of hierarchical materials that feature distinct structures at multiple length-scales, from nano to macro. For example, collagenous tissues are composed of a complex assembly of triple helical collagen molecules and provide the basis for materials such as bone, tendon or connective tissues in organs. The breakdown of these materials due to defects, mutations or large forces can have serious consequences on the functioning of organisms. For example, Alport Syndrome is a severe genetic disease characterized by the breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to eventual kidney failure in most patients. It is the second most inherited kidney disease in the United States, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level mechanisms of this disease, utilizing a bottom-up computational materiomics approach focused on the mutation associated with the most severe form of Alport Syndrome. 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. The purpose of this article is to review recent molecular dynamics simulations of structural and mechanical aspects of this disease at the single-molecule level (Srinivasan et al., Journal Of Structural Biology, 168(3), 503-510 (2010)), and to provide a general outlook into opportunities and challenges in the field of using molecular mechanics to improve our understanding of disease mechanisms (Buehler and Yung, Nature Materials, 8(3), 175-188 (2009)). We review a series of full-atomistic simulations in explicit solvent, which reveal the effects of single-residue glycine substitution mutations in a short segment of a collagen type IV tropocollagen molecule. 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 response and stiffness. We also provide a general discussion on computational approaches to study the link between genetics and functional mechanical properties of tissues.

Original languageEnglish (US)
Pages (from-to)755-770
Number of pages16
JournalMathematics and Mechanics of Solids
Volume15
Issue number7
DOIs
StatePublished - Sep 2010

Keywords

  • Alport Syndrome
  • Nanomechanics
  • breakdown
  • defects
  • failure
  • flaws
  • genetic disease
  • materiomics
  • protein material

ASJC Scopus subject areas

  • Mathematics(all)
  • Materials Science(all)
  • Mechanics of Materials

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