Coarse-Grained Modelling of DNA-Protein Interactions

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Proteins perform a vast array of essential biological functions within every living organism. In the context of the cell, they do not perform their function as individual entities, but in complexes with other biomacromolecules. Consequently, the focus of modern structural genomics is rapidly shifting toward the study of macromolecular DNA-protein complexes, which are at the origin of many infectious diseases, genetic disorders, and cancer.While established experimental high-resolution techniques like small-angle X-ray scattering (SAXS) provide a static view of DNA-protein complexes, computer simulations are often the only tool capable of providing key dynamic information of how these complexes perform their functions. Coarse-grained (CG) models, which reproduce the relevant structural features and thermodynamic properties at greatly reduced computational costs play here a particularly important role. As biology is known for having the largest and most complex structures in nature, CG models are not only an efficient alternative to atomistic approaches. They are indispensable for modelling biomacromolecules such as long DNA strands and large proteins on timescales in the millisecond range and beyond.During the last decade striking progress has been made in each separate field, CG modelling of DNA on one side, and CG modelling of proteins on the other side. The oxDNA model [1] (see Methodology) has emerged as the leading CG model of DNA and RNA. Similarly, the Associative Memory, Water-Mediated, Structure and Energy Model (AWSEM, see Methodology) is among the most successful CG protein models to date. Both models are implemented in the Large-scale Atomic/Molecular Massively Parallel Simulator [2 - 4] (LAMMPS, see Methodology), a global community molecular dynamics code, but cannot be used in conjunction. This leaves the emerging field of DNA-protein interactions inaccessible, which is in principle much broader than DNA and proteins alone.This project will develop both the theoretical concepts and software implementations of a coupling of the oxDNA and AWSEM models. Through the combined use of the two individually forthcoming models and the produced software it will constitute a transformative step in the emerging field of CG modelling of DNA-protein interactions, enable simulations on very long time and large length scales, and bring together growing scientific communities in structural biology, DNA and protein modelling, synthetic biology and nanotechnology. The new functionality will be directly applied to projects related to antimicrobial resistance and DNA nanotechnology.