383671 Calculation of Relative Folding Free Enthalpies of Amide-to-Ester Mutants of a Small Protein

Monday, November 17, 2014: 9:55 AM
Crystal Ballroom A/F (Hilton Atlanta)
Andreas Eichenberger1, Wilfred F. van Gunsteren1, Sereina Riniker1, Lukas von Ziegler1 and Niels Hansen1,2, (1)Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, Zurich, Switzerland, (2)Institute of Thermodynamics and Thermal Process Engineering, University of Stuttgart, Stuttgart, Germany

The effect of removing a hydrogen-bond donor from the backbone of the 34-residue WW domain of the protein Pin1 is investigated for 20 residues that are part of the three-stranded β-sheet fold of this protein in aqueous solution. Forty-eight molecular dynamics (MD) simulations of the wild-type protein and 20 amide-to-ester mutants started from the X-ray crystal structure and the NMR solution structure are analyzed in terms of backbone-backbone hydrogen bonding and differences in free enthalpies of folding in order to provide a structural interpretation of the experimental chaotrope and thermal denaturation data available [1] for this protein and the 20 mutants. The forty enveloping distribution sampling (EDS) [2-5] simulations of the 20 mutants link the structural Boltzmann ensembles to relative free enthalpies of folding between mutants and wild-type protein. The contribution of the different β-sheet hydrogen bonds to the relative stability of the mutants with respect to wild type cannot be directly inferred from thermal denaturation temperatures or free enthalpies of chaotrope denaturation for the different mutants, because some β-sheet hydrogen bonds show sizeable variation in occurrence between the different mutants. A proper representation of unfolded state conformations appears to be essential for an adequate description of relative stabilities of protein mutants.

References
[1] S. Deechongkit, P. Dawson, J. Kelly, J. Am. Chem. Soc., 2004, 126, 16762-16771.
[2] C.D. Christ, W.F. van Gunsteren, J. Chem. Phys., 2007, 126, 184110.
[3] C.D. Christ, W.F. van Gunsteren, J. Chem. Theory Comput., 2009, 5, 276-286.
[4] S. Riniker, C.D. Christ, N. Hansen, A.E. Mark, P.C. Nair, W.F. van Gunsteren, J. Chem. Phys., 2011, 135, 024105.
[5] N. Hansen, J. Dolenc, M. Knecht, S. Riniker, W.F. van Gunsteren, J. Comput. Chem., 2012, 33, 640-651.


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