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Topological descriptions of protein folding.

ABSTRACT: How knotted proteins fold has remained controversial since the identification of deeply knotted proteins nearly two decades ago. Both computational and experimental approaches have been used to investigate protein knot formation. Motivated by the computer simulations of Bölinger et al. [Bölinger D, et al. (2010) PLoS Comput Biol 6:e1000731] for the folding of the [Formula: see text]-knotted ?-haloacid dehalogenase (DehI) protein, we introduce a topological description of knot folding that could describe pathways for the formation of all currently known protein knot types and predicts knot types that might be identified in the future. We analyze fingerprint data from crystal structures of protein knots as evidence that particular protein knots may fold according to specific pathways from our theory. Our results confirm Taylor's twisted hairpin theory of knot folding for the [Formula: see text]-knotted proteins and the [Formula: see text]-knotted ketol-acid reductoisomerases and present alternative folding mechanisms for the [Formula: see text]-knotted phytochromes and the [Formula: see text]- and [Formula: see text]-knotted proteins.

SUBMITTER: Flapan E

PROVIDER: S-EPMC6510998 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Topological descriptions of protein folding.

Flapan Erica E He Adam A Wong Helen H

Proceedings of the National Academy of Sciences of the United States of America 20190418 19

How knotted proteins fold has remained controversial since the identification of deeply knotted proteins nearly two decades ago. Both computational and experimental approaches have been used to investigate protein knot formation. Motivated by the computer simulations of Bölinger et al. [Bölinger D, et al. (2010) <i>PLoS Comput Biol</i> 6:e1000731] for the folding of the [Formula: see text]-knotted α-haloacid dehalogenase (DehI) protein, we introduce a topological description of knot folding that ...[more]

PMID: 31000594

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Project description:Background: Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such a protein folding machine might include direct manipulation of the peptide backbone. Methods: To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Results: Remarkably, the addition of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments.

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Topological descriptions of protein folding.

Publications

Topological descriptions of protein folding.

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