Molecular Dynamics (MD) simulations have been recognized as a powerful and convenient tool for the study of the forces and mechanisms present in biological systems. Sampling large conformational transitions (e.g. folding, binding) remains challenging with MD. Recently, MELD (Modelling by Employing Limited Data) has emerged as a new way to accelerate sampling and guide MD simulations using information, thus driving the system to regions of configuration space compatible with experimental data or coarse physical insights. MELD has been successfully used to predict protein folding as well as protein-peptide binding poses and binding free energies, however, its ability to predict protein-DNA binding still remains to be unveiled.<br/>In this study, we report evidence of how MELD-accelerated molecular dynamics can be applied to search for binding modes and evaluate binding free energies for several families of transcription factors (TF) binding to DNA. In addition, a great effort has been put in the analysis of induce fit <i>vs.</i> conformational selection binding modes. For this purpose we have used AMBER ff14sb and GBneck2nu in combination with parmbsc1 modification. Our results indicate an overall good agreement with experimental structures when considering binding mode prediction. Physics based tools for capturing TF-DNA binding have been limited by force field and sampling issues. This work highlights MELD as a promising and powerful tool for the study of this and other biological phenomena associated to protein-DNA binding such as epigenetic modifications.

Unveiling the full binding pathway of TF-DNA complexes using MELD-accelerated molecular dynamics

2019 Spring National Meeting

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