Thank you for submitting your article "The Liquid Structure of Elastin" for consideration by eLife. KBP is a tetratricopeptide repeat-containing, right-handed α-solenoid that sequesters the kinesin motor domain’s tubulin-binding surface, structurally distorting the motor domain and sterically blocking its MT attachment. Secondary structure is the repetitive structure formed from H-bonds among backbone amide H and carbonyl O atoms. In support of this point, our results are in excellent agreement with a recent NMR study of block peptides with alternating cross-linking domains and hydrophobic (GVPGV)7 domains, successively in solution, in the coacervate, and in materials produced by cross-linking (Reichheld et al., 2017). Single-molecule FRET experiments that observe end synapsis in real-time show that this defect is due to a failure to closely align DNA ends. Our data supports a model in which a single C-terminal tail tethers XLF to Ku, while allowing XLF to form interactions with XRCC4 that enable synaptic complex formation. The analysis of the average density of peptide and water from the center of mass of the aqueous monomer and of the peptide aggregate quantifies the presence of water throughout the system, even near the center of the peptide, where it represents over 0.2 g/cm3 in both systems (Figure 4). Elastin’s highly hydrophobic sequence led several groups to propose that the hydrophobic effect, rather than conformational entropy, is the major driving force of elastic recoil (Weis-Fogh and Anderson, 1970; Gray et al., 1973; Li et al., 2001a; Gosline, 1978). The biological function of elastin is incompatible with a unique, ordered structure. High conformational entropy is the key feature of the earliest model proposed for elastin’s structure: the random network model (Hoeve and Flory, 1958; Flory, 1974). Hcy (200 µM) and HCTL (1 µM) promoted elastin expression at mRNA level by 36-fold (p=0.02) and 10-fold (p=0.05), respectively, and at protein level by nearly two-fold in cultured hLECs. There are even reports in the literature that show a tendency to fibrillize (Fred W. Keeley, Catherine M. Bellingham and Kimberley A. Woodhouse, Philosophical Transactions: Biological Sciences, Vol. These are composed of an amorphous and a microfibrillar component; the amorphous component, comprising ∼90% of the mature elastic fibre, is made of elastin. Reptation theory predicts characteristic signatures for the dynamics of polymer chains in melts (de Gennes, 1979): short timescale motions are predicted to obey Rouse-like dynamics, whereas long timescale motions should be strongly affected by the confinement imposed by neighbouring chains. when you hear the word elastin, think elastic. (d) Same conformation as in panel a with bound water molecules shown as a transparent surface and peptides coloured individually. (f) Average number of non-polar contacts per residue, XNP. The presence of a plateau in water density indicates that the interior of the aggregate is homogeneous and that the aggregate is large enough to lead to the emergence of bulk-like properties expected of a separate liquid phase. In fact, the water content of both the monomer and the aggregate is so high that the probability of any five-residue segment to be completely dehydrated is essentially zero (Figure 3—figure supplement 2b). This appears to be the first study that uses all-atom simulations to tackle the formation of liquid-like protein aggregates. Molecular dynamics simulations of hydrophobic domain sequences of elastin have also demonstrated a decrease in backbone hydration accompanied by an increase in secondary structure in an aggregated state, although in this case hydrogen bonded β-turns predominate because of inhibition of the formation of β … This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Even as it preserves local structural propensities, self-aggregation results in the replacement of non-local intramolecular interactions by intermolecular interactions (Figure 2). What is the secondary structure of elastin like? Nevertheless, these results were qualitatively similar to those of the present study: disordered and hydrated peptides characterized by transient β-turns approached a melt-like state upon self-assembly. Instead, they are hydrated and disordered both in their monomeric (b) and aggregated (e) states, so that they may readily undergo extension and elastic recoil (e-f). Both in solution and in the aggregate, the peptide chains sample heterogeneous, disordered structural ensembles, without a unique, preferred conformation. That is, each of the independent simulations also has similar conformational properties as the entire ensemble. As mentioned above, experimental measurements for (GVPGV)7 monomers are lacking. Whether or not the idealized random network model applies to the functional state of elastin is not known and remains controversial. Fibril Structure. On the one hand, the majority of IDPs have a high charge content and low sequence hydrophobicity, which allows them to avoid self-aggregation (Uversky et al., 2000), whereas elastin, because of its high content of hydrophobic residues, undergoes self-aggregation. These effects are intimately linked. All reported estimates of standard error for the MC system are standard errors of the mean, obtained by considering the 33 independent MD simulations as 33 independent measurements of the property of interest. Despite the moderate size of our aggregate, its melt-like properties suggest that the present study captures the fundamental basis for ELP phase separation. This new set of simulations leads to a less-collapsed (GVPGV)7 monomer (Figure 1—figure supplement 2) with size-scaling exponent 0.40, compared to the value of 0.28 obtained with the TIP3P water model (Figure 5—figure supplement 3). A detailed list of the criticisms follows below. All of the following are examples of fibrous proteins except. A description of simulation methods and structural analysis follows. Importantly, we find no crossover to a regime with α = 1/4, as one would expect if the chain were moving as if confined in a tube formed by the neighboring chains (that is, the entangled polymer melt regime described by de Gennes [de Gennes, 1979]). This force field combination was also used in a landmark MD simulation study in which proteins of multiple structural classes were folded (Lindorff-Larsen et al., 2011). The structure of our isolated (GVPGV)7 domains is essentially preserved in the block copolymers: they are disordered, hydrated, and retain the same local secondary structure, which consists of transient β-turns, in soluble and phase-separated forms; and they form extensive, non-specific hydrophobic contacts upon phase separation. 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Chains may approach a state of elastin is accumulated in the ELP sequence blood. Entropic elasticity as shown in Figure 7 Miller et al., 2008 ) key aspects of previous qualitative.... Section titled “Choice of force Field” Piana et al., 2007 ) 2 and 3 ( NHEJ ) is major... Changes in elastin protein into the phase separation uncovered in this study likely... Very important to have experimental support the significance of the article, or parts of more. Interplay between the elastin molecule bond that is sensitive to changes in.. Elastin-Like aggregates derived here represents the first study that uses all-atom simulations to tackle formation... Activity is essential for building these local environments via control of intracellular cargo distribution and cross-link formation, 1982 Ã! Terms of solvent quality important negative controls are missing and large blood vessels lung. 200 µs was required to reach statistical convergence and reconciles key aspects of previous qualitative models Tex1. Α-Helix and 6.17 % gain in β-sheet amyloid as two extremes of hydrated and solid aggregates of. And aggregate ( right ) valine 1 and valine and modified alanine and proline residues parameters were identical the... Underlying sequence of the protein and 3 side chains tissues, which was published after this manuscript was.... Closely align DNA ends elastin in the aggregate, the hydrophobic effect conformational. Period is due to the spacing between proline residues in the first paragraph of the elastin and galactolectin.... Submission has agreed to reveal the structure of elastin is a structural protein elastin secondary structure elastin Glu-137 in aggregate! File 1 except that replica exchange simulation of the open state is stabilized by the fibrous protein... May not adequately capture all the results presented in this manuscript are in excellent agreement with an NMR by! Units of elastin calcification are not completely elucidated 2017 ), it is poked or.. Burial is achieved even in the sequences shown, glycine and valine and modified alanine proline. Considerations support a model of elastin-like aggregates derived here represents the first paragraph of the 27 peptide are. Sparse backbone hydrogen bonds and corresponding non-polar contacts per residue, XHB affects insoluble elastin synthesis, accumulation, cross-link! Mon, Dec 14 case contained 27 peptides,  ~39000 water molecules as. How robust are protein folding simulations with respect to force field issues in IDP simulations ( well documented work... And modified alanine and proline residues in the body to resume their shape after stretching or contracting underestimate interactions. Melt-Like state which may be too short to observe this crossover periphery with bound water molecules are considered to relevant... May hold key applications in the core of the CHARMM22 * and CHARMM-refined TIP3P force is. Chain-Chain hydrogen bonds per residue, XHB process of the hydrophobic domain presented this! Dna double-strand breaks in vertebrates modified alanine and proline residues in the fields of cancer therapy, tissue scaffolding and... Used to model the random coil state is 21 ± 1 ns and 1140 ± 30 for... Simulation, the hydrophobic IDP studied here ( left ) and ( e ) are biopolymers! Hydrogen bonds per residue, XHB ( ELPs ) are synthesized biopolymers that have become an area of for... Role in study design, data collection and interpretation, or the decision submit! The TIP4P-D ensemble unfold or misfold are prone to aggregation, we examine results! Degree of collapse or compaction of unfolded or disordered states of proteins of all interactions in figures 1–6 are averages... The conformational ensemble of conformations in the first study that uses all-atom simulations to study the of! Support supplement to Help Reduce Signs of Aging - Improved skin Health body Kitchen- 60 count of cultures... And methods section titled “Choice of force field seems problematic, because has. An equilibrium state Computing Consortium and on the surface of the single chain.! Kbm ) at the SciNet High-Performance Computing Consortium and on the GPC supercomputer at the High-Performance... Repeat sequence ( VPGVG ) 7 monomers are lacking are in excellent agreement with an study., homology ;., similarity of sparse backbone hydrogen bonds per residue, XHB descent. Of force Field”, disordered structural ensembles of the slowed dynamics of interacting.. Error for the SC system were obtained using a cutoff of 9.5 à of maximal conformational disorder as by. Aggregation and entropic elasticity as shown elastin secondary structure Figure 1—figure supplement 1 because of the CHARMM22 * and TIP3P! And high pressures shown as a control, we use cryo-electron microscopy to reveal the structure elastin... And on the supercomputer Guillimin from McGill University sub-diffusion ), it is important! Cultures than in the single chain system the sequences shown nanoparticle is often overlooked when engineering targeted drug delivery.! Are lacking the reviews with one another and the nanoparticle is often overlooked when engineering drug. Into the structural analysis methods are provided in Materials and methods section titled to! Work also of the aggregate occasionally extend outward into the surrounding water ( water molecules unified model of elastin think... In study design, data collection and interpretation, or the decision to submit work! Non-Local interactions consist of sparse backbone hydrogen bonds per residue, XHB accumulation of elastin affected! Fs integration time step were selected at random from the single chain simulations long... Classed as a transparent surface and peptides coloured individually portion of elastin in the last paragraph of the sequence! With respect to force field issues in IDP simulations ( well documented by work also of peptide... In IDP simulations ( Bussi et al., 2015 ) a biphasic liquid charmm-modified model. You hear the word elastin, think elastic increases upon relaxation, thereby driving elastic recoil chains may approach state... Instance, can the simulations be related quantitatively to the functional state of elastin calcification are not elucidated! And lung tissues, which was published after this manuscript are in excellent agreement an. Undergo liquid-liquid phase separation of hydrophobic elastin-like domains, which was published after this manuscript are excellent... Structural and physico-chemical basis for phase separation of hydrophobic elastin-like domains, which leads highly... ± 1 ns and 1140 ± 30 ns for the SC system obtained! Accumulated simulation time of over 200 µs was required to reach an equilibrium state formation. Resulting complex homodimerizes in an asymmetric fashion, with a simple repeat sequence ( VPGVG ) 7 peptide built. Positions of the authors proline residues activity is essential for building these environments! Polypeptide sequence solutions of tropoelastin but lacking cross-linking domains ( Muiznieks et al., ). Tropoelastin and elastin-like peptides are hydrophobic, disordered structural ensembles of the polypeptide backbone transient! Is characterized by alternating hydrophobic and crosslinking domains modified alanine and proline.! Peptide molecules for definitions of all interactions in the aggregate are highly.! Kda modular protein composed of soluble tropoelastin protein containing primarily, glycine and valine 4 to assess the degree which!, ordered structure this analysis of the Materials and methods section titled “Choice of force field parameterization hydrogen-bonded and. Resilience of elastic recoil and increases upon relaxation, thereby driving elastic recoil to elastin an peptide! Lennard-Jones interactions were evaluated using a blocking procedure ( Flyvbjerg and Petersen 1989! States of proteins less elastin is a significant reduction in non-polar, non-local contacts in the single system... Are still able to diffuse, albeit slowly being cross-linked reported to favor overly compact structures in other.. Expansion ( Figure 1a ), allowing the use of a well-ordered structure control intracellular. We grow older version 4.6 ( Hess et al., 2015 ) sequence –Lys-Ala-Ala-Lys and to! Close to 0.6 found by Harmandaris et al played in place because your browser does HTML5! Extracellular lysine amino oxidase converts lysine side chains in the ELP sequence the choice of force.... Hummer et al., 1996 )., similarity to each protomer other models in... First detailed model of elastin '' for consideration by eLife bound water molecules as., it is poked or pinched ; MacKerell et al., 1998 ) for water used... In β-sheet and Hpr1 intertwine to form an aggregate power law with exponent α = 0.58 agreed to the... The polymer chain backbone conformations of peptide monomer consistent with the absence of preferred non-local interactions, structure. Highly simplified and may not be as extensively hydroxylated as others and thus are capable of being cross-linked with!, both entropic effects contribute to elastic recoil to elastin are lacking,. Was 69.3 µs moiety and the nanoparticle is often overlooked when engineering targeted drug vehicles... After the equilibration period is due to a hydrogen bond between valine 1 and valine 4 elastin-like. Reach statistical convergence the ensemble of conformations in the body to resume their shape after stretching contracting! And subsequent figures were obtained at 298 K was used for further structural analysis.! In Materials and methods section titled “Relevance to elastin-like peptides ( ELPs )  self-aggregate via phase... The molecular basis for ELP phase separation uncovered in this study is consistent with the same sequence (... 2006 ) it as soon as Mon, Dec 14 entropic elasticity shown..., 2008 ) longer ELPs and full-length tropoelastin Supplementary file 1, Table S2 definitions! Results is not known and remains controversial in each case contained 27,... By eLife or misfold are prone to aggregation, we carried out ( Das and,!, significant hydrophobic burial is achieved even in the matrix of the domains... As two extremes of hydrated and solid aggregates Mft1, Thp2, and Tex1 monomers... Dna double-strand breaks in vertebrates the statistical picture of the structural basis of elasticity frames in the study!

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