Journal article
The key to predicting the stability of protein mutants lies in an accurate description and proper configurational sampling of the folded and denatured states.
- Eichenberger AP Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland.
- van Gunsteren WF Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland. Electronic address: wfvgn@igc.phys.chem.ethz.ch.
- Riniker S Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland.
- von Ziegler L Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland.
- Hansen N Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland; Institute of Thermodynamics and Thermal Process Engineering, University of Stuttgart, D-70569 Stuttgart, Germany.
- 2014-09-21
Published in:
- Biochimica et biophysica acta. - 2015
Free energy
Hydrogen bonds
Molecular dynamics
Protein stability
Crystallography, X-Ray
Energy Transfer
Hydrogen Bonding
Kinetics
Molecular Dynamics Simulation
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Magnetic Resonance, Biomolecular
Peptidylprolyl Isomerase
Protein Denaturation
Protein Folding
Protein Stability
Protein Structure, Secondary
Protein Unfolding
English
BACKGROUND
The contribution of particular hydrogen bonds to the stability of a protein fold can be investigated experimentally as well as computationally by the construction of protein mutants which lack particular hydrogen-bond donors or acceptors with a subsequent determination of their structural stability. However, the comparison of experimental data with computational results is not straightforward. One of the difficulties is related to the representation of the unfolded state conformation.
METHODS
A series of molecular dynamics simulations of the 34-residue WW domain of protein Pin1 and 20 amide-to-ester mutants started from the X-ray crystal structure and the NMR solution structure are analysed in terms of backbone-backbone hydrogen bonding and differences in free enthalpies of folding in order to provide a structural interpretation of the experimental data available.
RESULTS
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 experimental 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.
CONCLUSIONS
A proper representation of unfolded state conformations appears to be essential for an adequate description of relative stabilities of protein mutants.
GENERAL SIGNIFICANCE
The simulations may be used to link the structural Boltzmann ensembles to relative free enthalpies of folding between mutants and wild-type protein and show that unfolded conformations have to be treated with a sufficient level of detail in free energy calculations of protein stability. This article is part of a Special Issue entitled Recent developments of molecular dynamics.
The contribution of particular hydrogen bonds to the stability of a protein fold can be investigated experimentally as well as computationally by the construction of protein mutants which lack particular hydrogen-bond donors or acceptors with a subsequent determination of their structural stability. However, the comparison of experimental data with computational results is not straightforward. One of the difficulties is related to the representation of the unfolded state conformation.
METHODS
A series of molecular dynamics simulations of the 34-residue WW domain of protein Pin1 and 20 amide-to-ester mutants started from the X-ray crystal structure and the NMR solution structure are analysed in terms of backbone-backbone hydrogen bonding and differences in free enthalpies of folding in order to provide a structural interpretation of the experimental data available.
RESULTS
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 experimental 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.
CONCLUSIONS
A proper representation of unfolded state conformations appears to be essential for an adequate description of relative stabilities of protein mutants.
GENERAL SIGNIFICANCE
The simulations may be used to link the structural Boltzmann ensembles to relative free enthalpies of folding between mutants and wild-type protein and show that unfolded conformations have to be treated with a sufficient level of detail in free energy calculations of protein stability. This article is part of a Special Issue entitled Recent developments of molecular dynamics.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/j.bbagen.2014.09.014
- PMID 25239199
- Persistent URL
- https://sonar.rero.ch/global/documents/267206
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