(63a) Relative Free Enthalpies for Point Mutations in Two Proteins With Highly Similar Sequence But Different Folds

Understanding the capability of a protein to change to a completely different fold as a result of minor mutagenic perturbation is central to understanding how new protein structures and functions evolve [1]. Currently the structures of protein sequences at the interface between folds cannot be predicted reliably with both ab initio and knowledge based prediction algorithms [1]. A pair of proteins derived from Streptococcus protein G, GA95 and GB95, that have different folds despite being different by only three amino acids [2] is one striking example demonstrating that small local changes can cause large global changes and has implications for sequence-based structure-prediction methods. To understand why the amino acid changes bring about this large conformational change we use molecular dynamics simulations in explicit solvent and employ the enveloping distribution sampling methodology [3,4] to calculate the changes in free enthalpy associated with point mutations in the two different folds. The results show that point mutations at different positions in the amino acid sequence do not contribute equally to the free enthalpy difference between the native and non-native sequence-structure combinations. The individual free-enthalpy changes are almost sequence independent in the four-strand/one-helix structure, the stable form of GB95, while in the three-helix bundle structure, the stable form of GA95, an interplay between residues 20 and 45 is observed, supporting the experimental findings for this protein.

[1] P. N. Bryan and J. Orban, Curr. Opin. Struct. Biol. (2013) http://dx.doi.org/10.1016/j.sbi.2013.03.001

[2] P. A. Alexander, Y. He, Y. Chen, J. Orban and P. N. Bryan, Proc. Natl. Acad. Sci. USA 106 (2009) 21149

[3] C. D. Christ and W. F. van Gunsteren, J. Chem. Phys. 126 (2007) 184110

[4] N. Hansen, J. Dolenc, M. Knecht, S. Riniker and W. F. van Gunsteren, J. Comput. Chem. 33 (2012) 640