Modeller: Generation and Refinement of Homology-Based Protein Structure Models

Fiser, András; Šali, Andrej

doi:10.1016/s0076-6879(03)74020-8

Cited by 1,537 publications

(1,242 citation statements)

References 73 publications

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“…The sequence of the human type I collagen is obtained from PubMed (entry number NP_000079 for α1(I) chain and NP_000080 for the α2(I) chain). The 3HR2 structure and the human collagen type I sequence are aligned, and ten homology models are built and scored by the Discrete Optimized Protein Energy (DOPE) using the Modeller program (version 9.6) [67]. The structure with the lowest DOPE value is chosen for building the collagen microfibril model.…”

Section: Homology Modellingmentioning

confidence: 99%

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Gautieri

Vesentini²,

Redaelli³

et al. 2011

Nano Lett.

573

488

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Abstract:Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al.(Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young's modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young's modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential.

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Section: Homology Modellingmentioning

confidence: 99%

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Gautieri

Vesentini²,

Redaelli³

et al. 2011

Nano Lett.

573

488

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“…To assess effects of mutations on structure and stability of granulin domains, we modeled the full structures of individual granulin domains based on the repetitive occurrence of the disulfide connected beta-hairpin stack motif (crystal structure PDB 1g26 [Tolkatchev et al, 2000b]) using SwissPDB-Viewer [Guex and Peitsch, 1997], Modeller [Fiser and Sali, 2003], ProQ [Wallner and Elofsson, 2003] and FoldX [Schymkowitz et al, 2005] (Fig. 2).…”

Section: In Silico Analysesmentioning

confidence: 99%

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

et al. 2007

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Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.

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“…3A for the LHR-ECD was generated using the MODELLER program (Fiser and Sali, 2003). The LRRs form a more open structure than that originally proposed (Bhowmick et al, 1996) and contain proposed structures for the N-and C-terminal cysteinerich regions, characterized, respectively, by the presence of two antiparallel β strands and α helices/parallel β strand that is aligned to the last β strand in the LRR.…”

Section: The Lhr-ecd: Structure and Hormone Bindingmentioning

confidence: 99%

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

Puett

DeMars

et al. 2007

Molecular and Cellular Endocrinology

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The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800-900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteinerich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR-ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG-LHR-Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH-FSHR-ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein-protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR-ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1-3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG-LHR-Gs, but considerable progress has been made in the past few years.

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Modeller: Generation and Refinement of Homology-Based Protein Structure Models

Cited by 1,537 publications

References 73 publications

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

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