Osteogenesis imperfecta mutations lead to local tropocollagen unfolding and disruption of H-bond network

Gautieri, Alfonso; Vesentini, Simone; Redaelli, Alberto; Buehler, Markus J.

doi:10.1039/c2ra01047j

Cited by 14 publications

(9 citation statements)

References 49 publications

(60 reference statements)

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“…The systems were modeled following protocols described in previous studies [33,34,35,36,37]. They were all minimized and equilibrated for 100 ps using the NAMD code [38] under constant pressure and temperature (NPT) to relax the volume of the periodic box.…”

Section: Methodsmentioning

confidence: 99%

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Gautieri

Beeg

Gobbi

et al. 2019

IJMS

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The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer’s disease.

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Section: Methodsmentioning

confidence: 99%

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Gautieri

Beeg

Gobbi

et al. 2019

IJMS

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“…Obtained results are in the same order of magnitude as the mesoscale simulations presented in Refs. [9,47], where the values of Young moduli are reported to be between 4.36 and 6 GPa. The lower values of the elastic moduli reported in these articles, result from lower strain-rates ranges.…”

Section: Resultsmentioning

confidence: 99%

Molecular-based nonlinear viscoelastic chemomechanical model incorporating thermal denaturation kinetics of collagen fibrous biomaterials

Młyniec

Tomaszewski

Spiesz

et al. 2015

Polymer Degradation and Stability

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“…Collagen self-assembly occurs on differing hierarchical levels. Collagen molecules reach their fibrillar structure by a process referred to as self-assembly where positional relationships align based on physico-chemical factors rather than biologic cellular direction ( Kar et al, 2006 ; Gautieri et al, 2012 ). This process is maintained in OI but the collagen molecular mutations eventually affect fibril structure.…”

Section: Discussionmentioning

confidence: 99%

Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy

et al. 2021

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Diaphyseal long bone cortical tissue from 30 patients with lethal perinatal Sillence II and progressively deforming Sillence III osteogenesis imperfecta (OI) has been studied at multiple levels of structural resolution. Interpretation in the context of woven to lamellar bone formation by mesenchymal osteoblasts (MOBLs) and surface osteoblasts (SOBLs) respectively demonstrates lamellar on woven bone synthesis as an obligate self-assembly mechanism and bone synthesis following the normal developmental pattern but showing variable delay in maturation caused by structurally abnormal or insufficient amounts of collagen matrix. The more severe the variant of OI is, the greater the persistence of woven bone and the more immature the structural pattern; the pattern shifts to a structurally stronger lamellar arrangement once a threshold accumulation for an adequate scaffold of woven bone has been reached. Woven bone alone characterizes lethal perinatal variants; variable amounts of woven and lamellar bone occur in progressively deforming variants; and lamellar bone increasingly forms rudimentary and then partially compacted osteons not reaching full compaction. At differing levels of microscopic resolution: lamellar bone is characterized by short, obliquely oriented lamellae with a mosaic appearance in progressively deforming forms; polarization defines tissue conformations and localizes initiation of lamellar formation; ultrastructure of bone forming cells shows markedly dilated rough endoplasmic reticulum (RER) and prominent Golgi bodies with disorganized cisternae and swollen dispersed tubules and vesicles, structural indications of storage disorder/stress responses and mitochondrial swelling in cells with massively dilated RER indicating apoptosis; ultrastructural matrix assessments in woven bone show randomly oriented individual fibrils but also short pericellular bundles of parallel oriented fibrils positioned obliquely and oriented randomly to one another and in lamellar bone show unidirectional fibrils that deviate at slight angles to adjacent bundles and obliquely oriented fibril groups consistent with twisted plywood fibril organization. Histomorphometric indices, designed specifically to document woven and lamellar conformations in normal and OI bone, establish ratios for: i) cell area/total area X 100 indicating the percentage of an area occupied by cells (cellularity index) and ii) total area/number of cells (pericellular matrix domains). Woven bone is more cellular than lamellar bone and OI bone is more cellular than normal bone, but these findings occur in a highly specific fashion with values (high to low) encompassing OI woven, normal woven, OI lamellar and normal lamellar conformations. Conversely, for the total area/number of cells ratio, pericellular matrix accumulations in OI woven are smallest and normal lamellar largest. Since genotype-phenotype correlation is not definitive, interposing histologic/structural analysis allowin...

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Osteogenesis imperfecta mutations lead to local tropocollagen unfolding and disruption of H-bond network

Cited by 14 publications

References 49 publications

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Molecular-based nonlinear viscoelastic chemomechanical model incorporating thermal denaturation kinetics of collagen fibrous biomaterials

Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy

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