Tropoelastin is a Flexible Molecule that Retains its Canonical Shape

Abstract

in elastic tissues including blood vessels, skin, and lungs. [1,2] The mature form of the secreted human tropoelastin monomer is 60 kDa [3] and is composed of an alternating pattern of repetitive, hydrophobic glycine-, valine-, and proline-rich domains spread out between lysine-containing cross-linking domains. [4] Traditionally described as a largely disordered molecule, recent studies suggest that tropoelastin is a flexible molecule with a distinct nanostructure [5][6][7] that determines its structural and cell-adhesive properties.Tropoelastin's distinct nanostructure determines its propensity to assemble into higher-order structures (Figure 1) through elastogenesis. [8] Elastogenesis begins with self-assembly of the ≈15 nm monomers, a process called coacervation. [9] Self-assembly, naturally occurring at physiological pH and salt conditions at 37 °C, results in spherical structures from 200 nm to 6 µm in diameter. [9][10][11] Spherule formation through coacervation begins at the cell surface by surface-tethered tropoelastin molecules, until released for integration into the growing elastic fiber. Tropoelastin aggregates adhere to the cell surface through GAG-and integrin-mediated interactions at specific interaction sites. [12][13][14][15][16][17][18] Spherules are deposited on a microfibrillar scaffold where they are stabilized Tropoelastin Tropoelastin is the dominant building block of elastic fibers, which form a major component of the extracellular matrix, providing structural support to tissues and imbuing them with elasticity and resilience. Recently, the atomistic structure of human tropoelastin is described, obtained through accelerated sampling via replica exchange molecular dynamics simulations. Here, principal component analysis is used to consider the ensemble of structures accessible to tropoelastin at body temperature (37 °C) at which tropoelastin naturally self-assembles into aggregated coacervates. These coacervates are relevant because they are an essential intermediate assembly stage, where tropoelastin molecules are then cross-linked at lysine residues and integrated into growing elastic fibers. It is found that the ensemble preserves the canonical tropoelastin structure with an extended molecular body flanked by two protruding legs, and identifies variations in specific domain positioning within this global shape. Furthermore, it is found that lysine residues show a large variation in their location on the tropoelastin molecule compared with other residues. It is hypothesized that this perturbation of the lysines increases their accessibility and enhances cross-linking. Finally, the principal component modes are extracted to describe the range of tropoelastin's conformational fluctuation to validate tropoelastin's scissor-twist motion that was predicted earlier.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

Elastin‐Like Recombinamers: Deconstructing and Recapitulating the Functionality of Extracellular Matrix Proteins Using Recombinant Protein Polymers

“…Structural, tropoelastin has a flexible and asymmetric conformation in solution, which is characterized by an extended molecular body and two protruding legs (Figure 2a). [79,80] The main feature of the sequence of amino acids in tropoelastin is the alternating hydrophobic and hydrophilic domains ( Figure 2b). [76] The hydrophobic domains mainly comprise of the nonpolar glycine (G), proline (P), valine (V), and alanine (A) amino acid residues typically occurring in repeat amino acid combination motifs of GV, GVA, and PGV, with GVGVP, GGVP, and GVGVAP repeats being the most common.…”

“…A worm-like chain model has been proposed to model this single chain elastin property ( Figure 3). [78,80] The crosslinking of tropoelastin monomer into the elastin fibers reduces its ability to extend and increases its stiffness. [95] In a study summarizing the Young's moduli of different constructs of either tropoelastin alone or a composite of tropoelastin with other materials, [77] a fairly broad range (up to 20 MPa) was observed.…”

“…Structural, tropoelastin has a flexible and asymmetric conformation in solution, which is characterized by an extended molecular body and two protruding legs ( Figure a). [ 79,80 ]…”

Nanoengineering in biomedicine: Current development and future perspectives

“…The structures of proteins determined by specified sequences of amino acid building blocks and the related folding mechanism have been extensively investigated over the past few decades through MD simulations [44]. Elastin, an important type of protein materials, has exquisite flexibility and possesses inverse temperature transition with folded structural form at high temperatures, which motivates applications in drug delivery, shape change materials, and biomimetic devices [45,46]. Nanoengineering has enhanced the understanding of elasticity and recoil provided by elastin in body tissues [47].…”

Advances in enhanced sampling molecular dynamics simulations for biomolecules

“…Since REMD and its adaptations allow unconstrained enhanced sampling without setting specific CVs to use them, many applications of these methods exist, in-DOI:10.1063/1674-0068/cjcp1905091 c ⃝2019 Chinese Physical Society cluding the studies of protein folding [3,76], protein structural ensemble generation [77,78], protein-protein recognition mechanism [79], peptide-nanomaterials interaction [80,81], binding/unbinding kinetics [82], RNA structural dynamics [83], and polymers assembly [84].…”