Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein
- The c-Fosc-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 meltingThe c-Fosc-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.…
Author details: | Zhili Zuo, Neha S. Gandhi, Katja Maren ArndtORCiDGND, Ricardo L. Mancera |
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DOI: | https://doi.org/10.1002/bip.22099 |
ISSN: | 0006-3525 |
Title of parent work (English): | Biopolymers |
Publisher: | Wiley-Blackwell |
Place of publishing: | Hoboken |
Publication type: | Article |
Language: | English |
Year of first publication: | 2012 |
Publication year: | 2012 |
Release date: | 2017/03/26 |
Tag: | GBSA; MM; coiled-coil; free energy of binding; leucine zipper; molecular dynamics |
Volume: | 97 |
Issue: | 11 |
Number of pages: | 11 |
First page: | 899 |
Last Page: | 909 |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |