TY - GEN
T1 - Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen
AU - Srinivasan, Maya
AU - Uzel, Sebastien G M
AU - Gautieri, Alfonso
AU - Keten, Sinan
AU - Buehler, Markus J.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1557/proc-1187-kk01-09
DO - 10.1557/proc-1187-kk01-09
M3 - Conference contribution
AN - SCOPUS:77649086878
SN - 9781605111605
T3 - Materials Research Society Symposium Proceedings
SP - 17
EP - 22
BT - Structure-Property Relationships in Biomineralized and Biomimetic Composites
PB - Materials Research Society
T2 - 2009 MRS Spring Meeting
Y2 - 14 April 2009 through 17 April 2009
ER -