Empirical estimation of local dielectric constants: Toward atomistic design of collagen mimetic peptides

Pike, Douglas H.; Nanda, Vikas

doi:10.1002/bip.22644

Cited by 24 publications

(24 citation statements)

References 89 publications

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“…Linkers were modeled onto the high-resolution structure of a [(POG) 10 ] 3 CMP as x - x -His, x -His and His for the leading, central and lagging strands. Backbone torsions of x and histidine, and sidechain rotamers of histidine were sampled using the modeling platform protCAD 63, 64 for those that formed a tetrahedral His 3 -metal site. The optimal conformation identified in the linker sampling specified all x positions in an α-helical conformation ( f ≈ −60 ϕ , y ≈ −45 ϕ ).…”

Section: Resultsmentioning

confidence: 99%

Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides

Parmar

Xu²,

Pike³

et al. 2015

Biochemistry

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We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

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Section: Resultsmentioning

confidence: 99%

Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides

Parmar

Xu²,

Pike³

et al. 2015

Biochemistry

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“…Starting models for molecular dynamics simulations were constructed and geometrically optimized using the protCAD[ 26 , 27 ] (protein Computer Automated Design) software platform. The protCAD software and relevant structure files in PDB format are included in an online repository (d).…”

Section: Methodsmentioning

confidence: 99%

Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides

et al. 2016

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Recently, catalytic peptides were introduced that mimicked protease activities and showed promising selectivity of products even in organic solvents where protease cannot perform well. However, their catalytic efficiency was extremely low compared to natural enzyme counterparts presumably due to the lack of stable tertiary fold. We hypothesized that assembling these peptides along with simple hydrophobic pockets, mimicking enzyme active sites, could enhance the catalytic activity. Here we fused the sequence of catalytic peptide CP4, capable of protease and esterase-like activities, into a short amyloidogenic peptide fragment of Aβ. When the fused CP4-Aβ construct assembled into antiparallel β-sheets and amyloid fibrils, a 4.0-fold increase in the hydrolysis rate of p-nitrophenyl acetate (p-NPA) compared to neat CP4 peptide was observed. The enhanced catalytic activity of CP4-Aβ assembly could be explained both by pre-organization of a catalytically competent Ser-His-acid triad and hydrophobic stabilization of a bound substrate between the triad and p-NPA, indicating that a design strategy for self-assembled peptides is important to accomplish the desired functionality.

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“…Starting structures were derived from the low-resolution fulllength crystal structure of pig Tpm -PDB ID 1C1G (27). Rat, shrimp and lobster sequence were threaded onto this structure and subject to sidechain optimization in protCAD (28,29).…”

Section: Resultsmentioning

confidence: 99%

Phyla-specific Correlated Dynamics in Tropomyosin

James

Nanda

2018

Preprint

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Tropomyosin (Tpm) is a continuous α-helical coiled-coil homodimer that regulates actinomyosin interactions in muscle. We examined extended molecular simulations of four Tpms, two from the vertebrate phylum Chordata (rat and pig), and two from the invertebrate Arthropoda (shrimp and lobster), and found that despite extensive sequence and structural homology across metazoans, dynamic behaviorparticularly long range structural fluctuationswere clearly distinct between phyla. Vertebrate Tpms were flexible and sampled complex, multi-state conformational landscapes.Invertebrate Tpms were rigid, sampling highly constrained harmonic landscapes.Filtering of trajectories by PCA into essential subspaces showed significant overlap within but not between phyla. In vertebrate Tpms, hinge-regions decoupled long-range inter-helical motions and suggested distinct domains. In contrast, crustacean Tpms lacked significant long range dynamic correlationsbehaving more like a single rigid rod. Although Tpm sequence and structure has highly conserved over the last 0.6billion years since the split of ancestral bilateria into protostomes and deuterostomes, divergence seems to have occurred at the level of long-range correlated dynamics, reflecting adaptations to phyla-specific requirements of actin binding and muscle contraction.

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Empirical estimation of local dielectric constants: Toward atomistic design of collagen mimetic peptides

Cited by 24 publications

References 89 publications

Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides

Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides

Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides

Phyla-specific Correlated Dynamics in Tropomyosin

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