title: Calculations of the free energy of interaction of the c-Fos-c-Jun coiled coil: effects of the solvation model and the inclusion of polarization effects.
abstract: The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein-protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson-Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos-c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos-c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.
authors.affiliation: Curtin Health Innovation Research Institute, Western Australian Biomedical Research Institute, School of Biomedical Sciences and School of Pharmacy, Curtin University, GPO Box U1987, Perth WA 6845, Australia.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zuo
authors.forename: Neha S
authors.initials: NS
authors.lastname: Gandhi
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Mancera
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry* / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry* / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012997:Solvents