An evaluation of Poisson-Boltzmann electrostatic free energy calculations through comparison with experimental mutagenesis data.

Abstract:

:For systems involving highly and oppositely charged proteins, electrostatic forces dominate association and contribute to biomolecular complex stability. Using experimental or theoretical alanine-scanning mutagenesis, it is possible to elucidate the contribution of individual ionizable amino acids to protein association. We evaluated our electrostatic free energy calculations by comparing calculated and experimental data for alanine mutants of five protein complexes. We calculated Poisson-Boltzmann electrostatic free energies based on a thermodynamic cycle, which incorporates association in a reference (Coulombic) and solvated (solution) state, as well as solvation effects. We observe that Coulombic and solvation free energy values correlate with experimental data in highly and oppositely charged systems, but not in systems comprised of similarly charged proteins. We also observe that correlation between solution and experimental free energies is dependent on dielectric coefficient selection for the protein interior. Free energy correlations improve as protein dielectric coefficient increases, suggesting that the protein interior experiences moderate dielectric screening, despite being shielded from solvent. We propose that higher dielectric coefficients may be necessary to more accurately predict protein-protein association. Additionally, our data suggest that Coulombic potential calculations alone may be sufficient to predict relative binding of protein mutants.

journal_name

Biopolymers

journal_title

Biopolymers

authors

Gorham RD Jr,Kieslich CA,Nichols A,Sausman NU,Foronda M,Morikis D

doi

10.1002/bip.21644

subject

Has Abstract

pub_date

2011-11-01 00:00:00

pages

746-54

issue

11

eissn

0006-3525

issn

1097-0282

journal_volume

95

pub_type

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