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Biomacromolecules. 2018 Jul 9;19(7):2496-2505. doi: 10.1021/acs.biomac.8b00099. Epub 2018 Apr 30.

Sequence Directionality Dramatically Affects LCST Behavior of Elastin-Like Polypeptides.

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Department of Materials Science and Engineering , North Carolina State University , 911 Partners Way , Raleigh , North Carolina 27695 , United States.
Department of Biomedical Engineering , Duke University , P.O. Box 90281, Durham , North Carolina 27708 , United States.
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development , The Rockefeller University , New York , New York 10065 , United States.


Elastin-like polypeptides (ELP) exhibit an inverse temperature transition or lower critical solution temperature (LCST) transition phase behavior in aqueous solutions. In this paper, the thermal responsive properties of the canonical ELP, poly(VPGVG), and its reverse sequence poly(VGPVG) were investigated by turbidity measurements of the cloud point behavior, circular dichroism (CD) measurements, and all-atom molecular dynamics (MD) simulations to gain a molecular understanding of mechanism that controls hysteretic phase behavior. It was shown experimentally that both poly(VPGVG) and poly(VGPVG) undergo a transition from soluble to insoluble in aqueous solution upon heating above the transition temperature ( Tt). However, poly(VPGVG) resolubilizes upon cooling below its Tt, whereas the reverse sequence, poly(VGPVG), remains aggregated despite significant undercooling below the Tt. The results from MD simulations indicated that a change in sequence order results in significant differences in the dynamics of the specific residues, especially valines, which lead to extensive changes in the conformations of VPGVG and VGPVG pentamers and, consequently, dissimilar propensities for secondary structure formation and overall structure of polypeptides. These changes affected the relative hydrophilicities of polypeptides above Tt, where poly(VGPVG) is more hydrophilic than poly(VPGVG) with more extended conformation and larger surface area, which led to formation of strong interchain hydrogen bonds responsible for stabilization of the aggregated phase and the observed thermal hysteresis for poly(VGPVG).

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