Abstract
BackgroundProtein-DNA recognition underlies fundamental biological processes ranging from transcription to replication and modification. Herein, we present a computational study of the sequence modulation of internal dynamic properties and of intraprotein networks of aminoacid interactions that determine the stability and specificity of protein-DNA complexes.ResultsTo this aim, we apply novel theoretical approaches to analyze the dynamics and energetics of biological systems starting from MD trajectories. As model system, we chose different sequences of Zinc Fingers (ZF) of the Zif268 family bound with different sequences of DNA. The complexes differ for their experimental stability properties, but share the same overall 3 D structure and do not undergo structural modifications during the simulations. The results of our analysis suggest that the energy landscape for DNA binding may be populated by dynamically different states, even in the absence of major conformational changes. Energetic couplings between residues change in response to protein and/or DNA sequence variations thus modulating the selectivity of recognition and the relative importance of different regions for binding.ConclusionsThe results show differences in the organization of the intra-protein energy-networks responsible for the stabilization of the protein conformations recognizing and binding DNA. These, in turn, are reflected into different modulation of the ZF's internal dynamics. The results also show a correlation between energetic and dynamic properties of the different proteins and their specificity/selectivity for DNA sequences. Finally, a dynamic and energetic model for the recognition of DNA by Zinc Fingers is proposed.
Highlights
Protein-DNA recognition underlies fundamental biological processes ranging from transcription to replication and modification
Structural Parameters The time evolution of each protein’s atom-positional Root Mean Square Deviation (RMSD) from the initial Xray structures was evaluated after combining the data from the three independent trajectories for each complex, as described in Materials and Methods
The calculation of average RMSD values obtained by comparing all the structures visited by each trajectory with all the structures visited by the other trajectories yielded an average value of 0.2nm, showing high degrees of structural similarity among the different complexes
Summary
Protein-DNA recognition underlies fundamental biological processes ranging from transcription to replication and modification. We present a computational study of the sequence modulation of internal dynamic properties and of intraprotein networks of aminoacid interactions that determine the stability and specificity of protein-DNA complexes. Protein-DNA recognition mechanisms underlie the functioning and regulation of several cellular processes ranging from transcription to replication, modification and restriction. Initial studies concentrated on the despite significant progress at the experimental and theoretical level, the molecular determinants of the events at the basis of protein-DNA recognition have not been fully characterized. Our goal here is to study the applicability of novel theoretical/computational approaches to map the principal energetic interactions and internal dynamic properties of complexes to investigate the determinants of stability, selectivity and specificity of different mutants with the same 3 D organization for selected DNA sequences
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