Modeling of macromolecular interactions in the cell - Project Summary Recent developments in the protein structure prediction field showed that protein models can routinely reach unprecedented levels of near-experimental accuracy. In this context, modeling macromolecular interactions in the living cell is becoming more central than ever before. Classical techniques for modeling macromolecular interactions include docking and biomolecular simulations. While the latter can give access to the dynamics and the kinetics of the interactions, they are either relatively slow, if carried out at all-atom representation, or coarse- grained. Docking methods are more efficient, but do not account for the kinetics of the association. Our recent study bridged the two modeling methodologies to put forward an approach capable of reaching unprecedented simulation timescales at all-atom resolution. This proposal aims at advancing this approach in multiple directions that reflect the diversity and the scope of macromolecular interactions in the cell. To accomplish that, we will apply efficient simulation protocols to different types of macromolecules in all-atom representation to sample the intermolecular energy landscapes pre-computed by docking. The project will involve characterization of the intermolecular energy landscapes for different types of macromolecules; simulation of the macromolecular interactions by sampling the energy landscapes; development of public resources incorporating techniques developed in the project; and application of the simulation approaches to molecular systems of biological interest. The long-term goals are to gain insights into fundamental principles of molecular processes in living systems, including dynamics and kinetics of the macromolecular interactions and to develop adequate structural characterization of cells at extra-long timescales. The analysis of the intermolecular landscapes for different macromolecular types will benefit our understanding of their interaction and provide framework for the docking. Docking protocols will be advanced for adequate representation of the full intermolecular energy landscape, including the multiplicity of transient interactions. New simulators of crowded macromolecular environment will be developed to sample the energy landscape. The project will develop powerful approaches to modeling macromolecular interactions in the cell, publicly available to the scientific community, facilitating better understanding of the cellular mechanisms.
