Molecular dynamics simulation of the interaction between a peptide from papillomavirus E2 protein and DNA
Giesel, G. M.1, Lima, L. M. T. R.3, Faber-Barata, J3, Guimarães, J. A.1, and Verli, H1,2
Centro de Biotecnologia – UFRGS, Porto Alegre, RS1; Faculdade de Farmácia – UFRGS, Porto Alegre, RS2; Faculdade de Farmácia – UFRJ, Rio de Janeiro, RJ3
Transcriptional regulation depends on sequence-specific binding of regulatory proteins to their responsive elements, a binding ruled by the protein ability to detect base edges for specific contacts, DNA flexibility and intrinsic curvature. The regulatory protein E2 from papillomavirus is a dimeric β-barrel capable to induce a large deformation upon DNA through binding. Direct contacts are formed between the a-helix-1 of each monomer of the E2 proteins and the major grove of the palindrome DNA through an ACCG half-site. Previous studies (Faber-Barata et al., FEBS Lett. 2006) demonstrated that a small peptide, corresponding to the a-helix-1 (a1E2, resides 294 to 311) in the folded E2 dimer, is intrinsically unfolded when free in solution, but display full capability for specific DNA recognition. The present work aims to investigate, at the atomic level, the mechanisms for base sequence discrimination by a1E2 using molecular dynamics (MD) simulations.
In order to describe the conformational properties of a1E2, two MD simulations were performed: 1) isolated a1E2 in solution, and 2) a1E2 complexed to an ACCG containing DNA sequence. In both simulations the GROMACS simulation suite and the OPLS-AA/L all-atom force field were applied, in a 30.0ns MD. To monitor the progress of the performed simulations we evaluated the root mean square deviation, the root mean square fluctuations, and the residue ellipticity.
The data so obtained shows that α1E2 partially unfolds in aqueous solution. However, such unfolding does not occurs when the peptide is complexed to DNA, indicating that the contacts performed between the peptide and its binding site are the main responsible for the helix folding.
Our data described at the atomic level the conformational dependence of α1E2 on the surrounding medium, corroborating the previous observations of Faber-Barata and co-workers of an induced fit mechanism in E2 protein recognition by the target DNA sequence. These observations demonstrate that specific DNA binding is not strictly dependent on a previous helical conformation, which can be achieved by a previously unfolded polypeptide. Moreover, it demonstrates that the study of protein folding and recognition mechanisms can be assisted by MD simulations.
Supported by: CNPq and CAPES
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