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Conformation-driven strategy for resilient and functional protein materials.

ABSTRACT: The exceptional elastic resilience of some protein materials underlies essential biomechanical functions with broad interest in biomedical fields. However, molecular design of elastic resilience is restricted to amino acid sequences of a handful of naturally occurring resilient proteins such as resilin and elastin. Here, we exploit non-resilin/elastin sequences that adopt kinetically stabilized, random coil-dominated conformations to achieve near-perfect resilience comparable with that of resilin and elastin. We also show a direct correlation between resilience and Raman-characterized protein conformations. Furthermore, we demonstrate that metastable conformation of proteins enables the construction of mechanically graded protein materials that exhibit spatially controlled conformations and resilience. These results offer insights into molecular mechanisms of protein elastomers and outline a general conformation-driven strategy for developing resilient and functional protein materials.

SUBMITTER: Mu X

PROVIDER: S-EPMC8795527 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Conformation-driven strategy for resilient and functional protein materials.

Mu Xuan X Yuen John S K JSK Choi Jaewon J Zhang Yixin Y Cebe Peggy P Jiang Xiaocheng X Zhang Yu Shrike YS Kaplan David L DL

Proceedings of the National Academy of Sciences of the United States of America 20220101 4

The exceptional elastic resilience of some protein materials underlies essential biomechanical functions with broad interest in biomedical fields. However, molecular design of elastic resilience is restricted to amino acid sequences of a handful of naturally occurring resilient proteins such as resilin and elastin. Here, we exploit non-resilin/elastin sequences that adopt kinetically stabilized, random coil-dominated conformations to achieve near-perfect resilience comparable with that of resili ...[more]

PMID: 35074913

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Project description:The dopamine transporter (DAT), a member of the neurotransmitter:Na(+) symporter (NSS) family, terminates dopaminergic neurotransmission and is a major molecular target for psychostimulants such as cocaine and amphetamine, and for the treatment of attention deficit disorder and depression. The crystal structures of the prokaryotic NSS homolog of DAT, the leucine transporter LeuT, have provided critical structural insights about the occluded and outward-facing conformations visited during the substrate transport, but only limited clues regarding mechanism. To understand the transport mechanism in DAT we have used a homology model based on the LeuT structure in a computational protocol validated previously for LeuT, in which steered molecular dynamics (SMD) simulations guide the substrate along a pathway leading from the extracellular end to the intracellular (cytoplasmic) end.Key findings are (1) a second substrate binding site in the extracellular vestibule, and (2) models of the conformational states identified as occluded, doubly occupied, and inward-facing. The transition between these states involve a spatially ordered sequence of interactions between the two substrate-binding sites, followed by rearrangements in structural elements located between the primary binding site and the cytoplasmic end. These rearrangements are facilitated by identified conserved hinge regions and a reorganization of interaction networks that had been identified as gates.Computational simulations supported by information available from experiments in DAT and other NSS transporters have produced a detailed mechanistic proposal for the dynamic changes associated with substrate transport in DAT. This allosteric mechanism is triggered by the binding of substrate in the S2 site in the presence of the substrate in the S1 site. Specific structural elements involved in this mechanism, and their roles in the conformational transitions illuminated here describe, a specific substrate-driven allosteric mechanism that is directly amenable to experiment as shown previously for LeuT.

Dataset Information

Conformation-driven strategy for resilient and functional protein materials.

Publications

Conformation-driven strategy for resilient and functional protein materials.

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