Abstract
Modeling biomolecular assemblies is an important field in computational structural biology. The inherent complexity of their energy landscape and the computational cost associated with modeling large and complex assemblies are major drawbacks for integrative modeling approaches. The so-called coarse-graining approaches, which reduce the degrees of freedom of the system by grouping several atoms into larger “pseudo-atoms,” have been shown to alleviate some of those limitations, facilitating the identification of the global energy minima assumed to correspond to the native state of the complex, while making the calculations more efficient. Here, we describe and assess the implementation of the MARTINI force field for DNA into HADDOCK, our integrative modeling platform. We combine it with our previous implementation for protein-protein coarse-grained docking, enabling coarse-grained modeling of protein-nucleic acid complexes. The system is modeled using MARTINI topologies and interaction parameters during the rigid body docking and semi-flexible refinement stages of HADDOCK, and the resulting models are then converted back to atomistic resolution by an atom-to-bead distance restraints-guided protocol. We first demonstrate the performance of this protocol using 44 complexes from the protein-DNA docking benchmark, which shows an overall ~6-fold speed increase and maintains similar accuracy as compared to standard atomistic calculations. As a proof of concept, we then model the interaction between the PRC1 and the nucleosome (a former CAPRI target in round 31), using the same information available at the time the target was offered, and compare all-atom and coarse-grained models.
Highlights
Protein-DNA interactions play essential roles in cellular processes such as gene expression, regulation, transcription, DNA repair, or chromatin packaging in eukaryotes (Pandey et al, 2019)
We have integrated the MARTINI CG force field for nucleic acids into HADDOCK version 2.4, combining it with our previous implementation of the protein MARTINI CG force field (Monticelli et al, 2008), enabling full coarsegrained protein-DNA docking
In 1zme, we find an acceptable model at position 176 (i.e., Top 200 according to our analysis) with 0.11/7.85 Å/9.94 Å for fraction of common contacts (Fnat)/iRMSD/l-RMSD while the best alternative to standard atomistic (AA) model falls out the acceptable CAPRI criteria (0.04/7.51 Å/10.3 Å)
Summary
Protein-DNA interactions play essential roles in cellular processes such as gene expression, regulation, transcription, DNA repair, or chromatin packaging in eukaryotes (Pandey et al, 2019). Coarse-graining (CG) has been demonstrated to be a valuable alternative to standard atomistic (AA) approaches to alleviate some of those limitations and help the identification of the energy global minima by smoothing out the energy landscape (Hills et al, 2010; Roel-Touris et al, 2019). To this end, CG approaches group several atoms (either a few atoms or entire side chains) into larger “pseudo-atoms” or “beads,” which results into a reduction in the number of degrees of freedom of the system (Kmiecik et al, 2016). Protein or/and protein-nucleic acid coarse-grained approaches have been implemented in several docking/modeling software such as for example: CABS-dock (Blaszczyk et al, 2016) RosettaDock (Gray et al, 2003), IMP (Russel et al, 2012), ATTRACT (Setny et al, 2012), NPDock (Tuszynska et al, 2015), PyRy3D (genesilico.pl/pyry3d), and more recently in HADDOCK (Dominguez et al, 2003; RoelTouris et al, 2019), our integrative modeling platform
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