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Kramer, Rachel Z; Bella, Jordi; Mayville, Patricia; Brodsky, Barbara; Berman, Helen M.

doi:10.1038/8259

Cited by 282 publications

(42 citation statements)

References 35 publications

(36 reference statements)

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“…Although these measures were uniform in the ideal starting conformation, they vary along the length of the triple helix as a result of the simulation, in agreement with results from experimental studies revealing local variations in helical twist. 30, 31 …”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulations of the Full Triple Helical Region of Collagen Type I Provide an Atomic Scale View of the Protein's Regional Heterogeneity

Bodian

Radmer

Holbert³

et al. 2010

Biocomputing 2011

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Collagen is a ubiquitous extracellular matrix protein. Its biological functions, including maintenance of the structural integrity of tissues, depend on its multiscale, hierarchical structure. Three elongated, twisted peptide chains of >1000 amino acids each assemble into trimeric proteins characterized by the defining triple helical domain. The trimers associate into fibrils, which pack into fibers. We conducted a 10 ns molecular dynamics simulation of the full-length triple helical domain, which was made computationally feasible by segmenting the protein into overlapping fragments. The calculation included ~1.8 million atoms, including solvent, and took approximately 11 months using the CPUs of over a quarter of a million computers. Specialized analysis protocols and a relational database were developed to process the large amounts of data, which are publicly available. The simulated structures exhibit heterogeneity in the triple helical domain consistent with experimental results but at higher resolution. The structures serve as the foundation for studies of higher order forms of the protein and for modeling the effects of disease-associated mutations.

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Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulations of the Full Triple Helical Region of Collagen Type I Provide an Atomic Scale View of the Protein's Regional Heterogeneity

Bodian

Radmer

Holbert³

et al. 2010

Biocomputing 2011

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“…Docking studies were performed using a single-stranded, collagen α1(I)-like 15mer peptide with the Gly-Ile cleavage site incorporated in an attempt to better understand the functioning of the active enzyme. The peptide was modelled on the known structure of one of the chains of the triple-helical collagen (PDB code: 1BKV) 24 . Several solutions were generated.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of an Active Form of Human MMP-1

Iyer

Visse

Nagase

et al. 2006

Journal of Molecular Biology

104

122

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The extracellular matrix is a dynamic environment that constantly undergoes remodelling and degradation during vital physiological processes such as angiogenesis, wound healing, and development. Unbalanced extracellular matrix breakdown is associated with many diseases such as arthritis, cancer and fibrosis. Interstitial collagen is degraded by matrix metalloproteinases with collagenolytic activity by MMP-1, MMP-8 and MMP-13, collectively known as the collagenases. Matrix metalloproteinase 1 (MMP-1) plays a pivotal role in degradation of interstitial collagen types I, II, and III. Here, we report the crystal structure of the active form of human MMP-1 at 2.67 Å resolution. This is the first MMP-1 structure that is free of inhibitor and a water molecule essential for peptide hydrolysis is observed coordinated with the active site zinc. Comparing this structure with the human proMMP-1 shows significant structural differences, mainly in the relative orientation of the hemopexin domain, between the pro form and active form of the human enzyme.

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“…Residues 1–6 and 25–30 are GPO triplets that stabilize the ends. 15 For comparison, we also considered α chains made only of the GPO triplet. The mutant chains α1 (R21O) and α2 (O21R) had Arg21 of α1 and Hyp21 of α2 switched, to investigate the role of arginine for the triple helix stability.…”

Section: Computational Methodsmentioning

confidence: 99%

“…8,10,13,14 Labile domains are thought to be more loosely wound and flexible compared to the imino-rich domain. 7,15,16 The collagen cleavage site hydrolyzed by MMP is located in a labile domain, about 3/4 along the length of the molecule. 17,18 Since a well-folded collagen triple helix is highly resistant to protease cleavage, 17,19 local unfolding of the labile domain is critical for cleavage by MMP.…”

Section: Introductionmentioning

confidence: 99%

Chain Registry and Load-Dependent Conformational Dynamics of Collagen

Teng¹,

Hwang

2014

Biomacromolecules

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Degradation of fibrillar collagen is critical for tissue maintenance. Yet, understanding collagen catabolism has been challenging partly due to a lack of atomistic picture for its load-dependent conformational dynamics, as both mechanical load and local unfolding of collagen affect its cleavage by matrix metalloproteinase (MMP). We use molecular dynamics simulation to find the most cleavage-prone arrangement of α chains in a collagen triple helix and find amino acids that modulate stability of the MMP cleavage domain depending on the chain registry within the molecule. The native-like state is mechanically inhomogeneous, where the cleavage site interfaces a stiff region and a locally unfolded and flexible region along the molecule. In contrast, a triple helix made of the stable glycine-proline-hydroxyproline motif is uniformly flexible and is dynamically stabilized by short-lived, low-occupancy hydrogen bonds. These results provide an atomistic basis for the mechanics, conformation, and stability of collagen that affect catabolism.

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Abstract: The 2 A crystal structure reported here of the collagen-like model peptide, T3-785, provides the first visualization of how the sequence of collagen defines distinctive local conformational variations in triple-helical structure.

Cited by 282 publications

References 35 publications

Molecular Dynamics Simulations of the Full Triple Helical Region of Collagen Type I Provide an Atomic Scale View of the Protein's Regional Heterogeneity

Molecular Dynamics Simulations of the Full Triple Helical Region of Collagen Type I Provide an Atomic Scale View of the Protein's Regional Heterogeneity

Crystal Structure of an Active Form of Human MMP-1

Chain Registry and Load-Dependent Conformational Dynamics of Collagen

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