Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen
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Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen Maya Srinivasan1,2, Sebastien G.M. Uzel1,3, Alfonso Gautieri1,4, Sinan Keten1, Markus J. Buehler1,5† 1
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave. Room 1-235A&B, Cambridge, MA, USA 2 Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ, USA 3 Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA, USA 4 Cellular and Molecular Biomechanics Research Group, Department of Bioengineering, Politecnico di Milano, Via Golgi 39, 20133 Milan, Italy 5 Center for Computational Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA, USA † Corresponding author, [email protected]
ABSTRACT Alport Syndrome is a genetic disease characterized by the 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 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. Through full-atomistic simulations in explicit solvent, the effects of a single-residue glycine substitution mutation are studied 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 molecule’s stress-strain response and stiffness. INTRODUCTION Collagen, a ubiquitous tropohelical structural protein material, is found most commonly in muscle and bone, but is also present in the basement membranes of the kidney, cochlea, and the eye’s lenses [1-5]. Diseases associated with collagenous tissues have severe consequences, since collagen is responsible for the mechanical integrity of the structural building blocks of organisms [6-9]. Alport Syndrome, a usually fatal inherited kidney disease, is due to a catastrophic breakdown of the renal glomerular basement membrane (GBM) that is made up of collagen type IV molecules [7, 10]. Patients diagnosed with Alport Syndrome display varied symptoms, the most dramatic of which is untreatable kidney failure; other symptoms include deafness and ocular lesions [11-14]. Several genetic point mutations have been discovered to have a high
correlation with the disease manifestation. Alport Syn
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