Computational investigation of the effect of thermal perturbation on the mechanical unfolding of titin I27

Abstract

The emergence of single-molecule force measurement experiments has facilitated a better understanding of protein folding pathways and the thermodynamics involved. Computational methods such as steered molecular dynamics (SMD) simulations are helpful in providing atomistic level information on the unfolding pathways. Recent experimental studies have showed that combinations of single-molecule experiments with traditional methods such as chemical and/or thermal denaturation yield additional insights into the folding phenomenon. In this study, we report results from extensive computations (a total of about 60 SMD simulations with a total length of about 0.4 μs) that address the effect of thermal perturbation on the mechanical stability of the I27 domain of the protein titin. A wide range of temperatures (280–340 K) were considered for the pulling, which was done at both constant velocity and constant force using SMD simulations. Good agreement with experimental data, such as for the trends in changes in average force and the maximum force with respect to the temperature, was obtained. This study identifies two competing pathways for the mechanical unfolding of I27, and illustrates the significance of combining various techniques to examine protein folding.

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Acknowledgments

UDP thanks the Department of Biotechnology (DBT), Govt. of India, for the Innovative Young Biotechnologist Award. We acknowledge DBT for financial assistance (BT/03/IYBA/2010).

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Correspondence to U. Deva Priyakumar.

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ESM 1

Figures of force–extension profiles at different temperatures, probability distributions of the unfolding forces, extensions at peak force, changes in the hydrogen-bond distances during the rupture of BE, FG, and FC strands, and extension vs. time profiles from constant force SMD simulations. (DOC 2102 kb)

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Bung, N., Priyakumar, U.D. Computational investigation of the effect of thermal perturbation on the mechanical unfolding of titin I27. J Mol Model 18, 2823–2829 (2012). https://doi.org/10.1007/s00894-011-1298-7

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Keywords

  • Protein folding
  • Steered molecular dynamics
  • Denaturation
  • Mechanical stability
  • Titin I27
  • Folding pathways