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Nonnative Contact Effects in Protein Folding


A comprehensive understanding of protein folding includes the knowledge of the formation of individual secondary structures, tertiary structure, and the effects of nonnative contacts on these folding events. The measurement of these microscopic events has been posing challenges for experiment and molecular simulation. In this work, we performed enhanced sampling MD simulations for three proteins (NTL9, NuG2b, and CspA) and analyzed minimum free energy paths on multi-dimensional free energy landscapes to explore the underlying folding mechanisms. Consistencies can be seen between the present simulations and the existing experiments as well as other MD simulations. The quantitative analysis reveals nucleation-condensation folding mechanism indicating the concurrent build-up of secondary and tertiary structures for the three proteins and gives the detailed formation sequence of the individual native secondary structure elements. More importantly, nonnative contacts are generally observed among the proteins, creating nonnative environment to affect the folding of individual secondary structure elements. A general tendency is that the secondary structure element(s) involved in the heaviest level of nonnative contacts have the largest formation free energy barrier(s), corresponding to the rate-limiting step(s) of the folding for proteins that follow nucleation-condensation mechanism. In summary, while native contacts determine the folding mechanism and pathway, nonnative contacts play an important role in determining protein folding thermodynamics through influencing the free energies of individual secondary structure element formation.

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Publication details

The article was received on 09 Dec 2018, accepted on 10 May 2019 and first published on 10 May 2019

Article type: Paper
DOI: 10.1039/C8CP07524G
Phys. Chem. Chem. Phys., 2019, Accepted Manuscript

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    Nonnative Contact Effects in Protein Folding

    Q. Shao and W. Zhu, Phys. Chem. Chem. Phys., 2019, Accepted Manuscript , DOI: 10.1039/C8CP07524G

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