Elastin-Like Polypeptides for Biomedical Applications

Varanko, Anastasia Kristine; Su, Jonathan; Chilkoti, Ashutosh

doi:10.1146/annurev-bioeng-092419-061127

“…In some poly(styrene)block-poly(acrylic acid) (PS-PAA) studies, an increase in hydrophobic block length was also reported to stabilize vesicle structures with increasingly smaller diameters as the length of the hydrophobic segment increased (43,45). These previous reports are consistent with our observations, in which, for example, the W 2 F 4 -(GPO) 6 GG conjugate (with a longer hydrophobic ELP domain) formed smaller vesicles compared to conjugates with shorter ELP domains [e.g., W 2 F 2 -(GPO) 6 GG, W 2 F 3 -(GPO) 6 GG]. It is likely in these cases that a longer ELP domain occupies a larger volume and would induce greater interfacial curvature between the ELP and CLP domains so that smaller vesicles with a smaller number of ELP-CLPs would be formed (Fig.…”

Section: Morphological Features Of Elp-clp Conjugatessupporting

confidence: 91%

“…An important class of molecules developed for these applications is the elastin-like (poly)peptides (ELPs), which mimic features of the mammalian protein elastin, are composed largely of Val-Pro-Gly-Xaa-Gly amino acid repeat units (in which Xaa is any residue except proline) and exhibit the widely exploited lower-critical solution temperature ( 6 ) in which they are soluble in water below their transition temperature ( T t ) but will collapse into a coacervate phase above that temperature ( 7 ). ELPs have thus been enormously versatile as smart hydrophobic domains in thermally responsive peptide amphiphilic copolymers and in peptide conjugates ( 8 ) and have been investigated for manipulating T t in drug delivery systems and also for targeting cells via thermally responsive mechanisms ( 6 , 8 ). However, short synthetic ELPs with high inverse T t have been rarely studied as smart biomaterials for biological application ( 9 ), despite the versatility they would afford, largely because at low molecular-weights, the ELPs are fully soluble under physiologically relevant conditions and do not mediate assembly.…”

Section: Introductionmentioning

confidence: 99%

Fine structural tuning of the assembly of ECM peptide conjugates via slight sequence modifications

Qin

¹

,

Sloppy

²

,

Kiick

³

2020

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The self-assembly of nanostructures from conjugates of elastin-like peptides and collagen-like peptides (ELP-CLP) has been studied as means to produce thermoresponsive, collagen-binding drug delivery vehicles. Motivated by our previous work in which ELP-CLP conjugates successfully self-assembled into vesicles and platelet-like nanostructures, here, we extend our library of ELP-CLP bioconjugates to a series of tryptophan/phenylalanine-containing ELPs and GPO-based CLPs [W2Fx-b-(GPO)y] with various domain lengths to determine the impact of these modifications on the thermoresponsiveness and morphology. The lower transition temperature of the conjugates with longer ELP or CLP domains enables the formation of well-defined nanoparticles near physiological temperature. Moreover, the morphological transition from vesicles to platelet-like nanostructures occurred when the ratio of the lengths of ELP/CLP decreased. Given the previously demonstrated ability of many ELP-CLP bioconjugates to bind to both hydrophobic drugs and collagen-containing materials, our results suggest new opportunities for designing specific thermoresponsive nanostructures for targeted biological applications.

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“…9 summarizes results obtained for the two synthetic IDPs with UCST and LCST behavior. Recent attention has focused on IDPs derived from resilin- and elastin-like polypeptides that are designed to have UCST versus LCST behavior, respectively ( 31 , 81 ). We show results for two archetypal systems.…”

Section: Resultsmentioning

confidence: 99%

Connecting Coil-to-Globule Transitions to Full Phase Diagrams for Intrinsically Disordered Proteins

Zeng

¹

,

Holehouse

²

,

Chilkoti

³

et al. 2020

Biophysical Journal

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Phase separation is thought to underlie spatial and temporal organization that is required for controlling biochemical reactions in cells. Multivalence of interaction motifs, also known as stickers, is a defining feature of proteins that drive phase separation. Intrinsically disordered proteins with stickers uniformly distributed along the linear sequence can serve as scaffold molecules that drive phase separation. The sequence-intrinsic contributions of disordered proteins to phase separation can be discerned by computing or measuring sequence-specific phase diagrams. These help to delineate the combinations of protein concentration and a suitable control parameter, such as temperature, that support phase separation. Here, we present an approach that combines detailed simulations with a numerical adaptation of an analytical Gaussian cluster theory to enable the calculation of sequence-specific phase diagrams. Our approach leverages the known equivalence between the driving forces for single-chain collapse in dilute solutions and the driving forces for phase separation in concentrated solutions. We demonstrate the application of the theory-aided computations through calculation of phase diagrams for a set of archetypal intrinsically disordered low-complexity domains. We also leverage theories to compute sequence-specific percolation lines and thereby provide a thermodynamic framework for hardening transitions that have been observed for many biomolecular condensates.

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“…Finally, Figure 8 summarizes results obtained for the two synthetic IDPs with UCST and LCST behavior. Recent attention has focused on IDPs derived from resilin-and elastin-like polypeptides that are designed to have UCST versus LCST behavior, respectively [29,73]. We show results for two archetypal systems.…”

Section: Phase Diagrams For Polyq and Synthetic Idpsmentioning

confidence: 97%

Connecting coil-to-globule transitions to full phase diagrams for intrinsically disordered proteins

Zeng

¹

,

Holehouse

²

,

Chilkoti

³

et al. 2020

Preprint

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Phase separation is thought to underlie spatial and temporal organization that is required for controlling biochemical reactions in cells. Multivalence of interaction motifs also known as stickers is a defining feature of proteins that drive phase separation. Intrinsically disordered proteins with stickers uniformly distributed along the linear sequence can serve as scaffold molecules that drive phase separation. The sequence-intrinsic contributions of disordered proteins to phase separation can be discerned by computing or measuring sequence-specific phase diagrams. These help to delineate the combinations of protein concentration and a suitable control parameter such as temperature that support phase separation. Here, we present an approach that combines detailed simulations with a numerical adaptation of an analytical Gaussian cluster theory to enable the calculation of sequence-specific phase diagrams. Our approach leverages the known equivalence between the driving forces for single chain collapse in dilute solutions and the driving forces for phase separation in concentrated solutions. We demonstrate the application of the theory-aided computations through calculation of phase diagrams for a set of archetypal intrinsically disordered low complexity domains. STATEMENT OF SIGNIFICANCEIntrinsically disordered proteins that have the requisite valence of adhesive linear motifs can drive phase separation and give rise to membraneless biomolecular condensates. Knowledge of how phase diagrams vary with amino acid sequence and changes to solution conditions is essential for understanding how proteins contribute to condensate assembly and dissolution. In this work, we introduce a new two-pronged computational approach to predict sequence-specific phase diagrams. This approach starts by extracting key parameters from simulations of single-chain coilto-globule transitions. We use these parameters in our numerical implementation of the Gaussian cluster theory (GCT) for polymer solutions to construct sequences-specific phase diagrams. The method is efficient and demonstrably accurate and should pave the way for high-throughput assessments of phase behavior.

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Elastin-Like Polypeptides for Biomedical Applications

Cited by 199 publications

References 140 publications

Fine structural tuning of the assembly of ECM peptide conjugates via slight sequence modifications

Fine structural tuning of the assembly of ECM peptide conjugates via slight sequence modifications

Connecting Coil-to-Globule Transitions to Full Phase Diagrams for Intrinsically Disordered Proteins

Connecting coil-to-globule transitions to full phase diagrams for intrinsically disordered proteins

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