Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein.
The c-Fos-c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.
School of Biomedical Sciences, Curtin University, Perth, WA 6845, Australia.
Zhili
Z
Zuo
Neha S
NS
Gandhi
Katja M
KM
Arndt
Ricardo L
RL
Mancera
D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D016350:Leucine Zippers; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry*; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry*; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun