Saturation Mutagenesis by Efficient Free-Energy Calculation

Single-point mutations in proteins can greatly influence protein stability, binding affinity, protein function or its expression per se. Here, we present accurate and efficient predictions of the free energy of mutation of amino acids. We divided the complete mutational free energy into an unchargin...

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Bibliographic Details
Published in:Journal of chemical theory and computation 2018-02, Vol.14 (2), p.894-904
Main Authors: Jandova, Zuzana, Fast, Daniel, Setz, Martina, Pechlaner, Maria, Oostenbrink, Chris
Format: Article
Language:English
Subjects:
Amino acids
Amino Acids - chemistry
Amino Acids - genetics
Approximation
Free energy
Molecular Dynamics Simulation
Mutagenesis
Mutation
Proteins
Solvation
Thermodynamics
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Summary:Single-point mutations in proteins can greatly influence protein stability, binding affinity, protein function or its expression per se. Here, we present accurate and efficient predictions of the free energy of mutation of amino acids. We divided the complete mutational free energy into an uncharging step, which we approximate by a third-power fitting (TPF) approach, and an annihilation step, which we approximate using the one-step perturbation (OSP) method. As a diverse set of test systems, we computed the solvation free energy of all amino acid side chain analogues and obtained an excellent agreement with thermodynamic integration (TI) data. Moreover, we calculated mutational free energies in model tripeptides and established an efficient protocol involving a single reference state. Again, the approximate methods agreed excellently with the TI references, with a root-mean-square error of only 3.6 kJ/mol over 17 mutations. Our combined TPF+OSP approach does show not only a very good agreement but also a 2-fold higher efficiency than full blown TI calculations.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.7b01099