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Computational methodologies are increasingly addressing modeling of the whole cell at the molecular level. Proteins and their interactions are the key component of cellular processes. Techniques for modeling protein interactions, thus far, have included protein docking and molecular simulation. The latter approaches account for the dynamics of the interactions but are relatively slow, if carried out at all-atom resolution, or are significantly coarse grained. Protein docking algorithms are far more efficient in sampling spatial coordinates. However, they do not account for the kinetics of the association (i.e., they do not involve the time coordinate). Our proof-of-concept study bridges the two modeling approaches, developing an approach that can reach unprecedented simulation timescales at all-atom resolution. The global intermolecular energy landscape of a large system of proteins was mapped by the pairwise fast Fourier transform docking and sampled in space and time by Monte Carlo simulations. The simulation protocol was parametrized on existing data and validated on a number of observations from experiments and molecular dynamics simulations. The simulation protocol performed consistently across very different systems of proteins at different protein concentrations. It recapitulated data on the previously observed protein diffusion rates and aggregation. The speed of calculation allows reaching second-long trajectories of protein systems that approach the size of the cells, at atomic resolution. 

Abstract Small angle X‐ray scattering (SAXS) measures comprehensive distance information on a protein's structure, which can constrain and guide computational structure prediction algorithms. Here, we evaluate structure predictions of 11 monomeric and oligomeric proteins for which SAXS data were collected and provided to predictors in the 13th round of the Critical Assessment of protein Structure Prediction (CASP13). The category for SAXS‐assisted predictions made gains in certain areas for CASP13 compared to CASP12. Improvements included higher quality data with size exclusion chromatography‐SAXS (SEC‐SAXS) and better selection of targets and communication of results by CASP organizers. In several cases, we can track improvements in model accuracy with use of SAXS data. For hard multimeric targets where regular folding algorithms were unsuccessful, SAXS data helped predictors to build models better resembling the global shape of the target. For most models, however, no significant improvement in model accuracy at the domain level was registered from use of SAXS data, when rigorously comparing SAXS‐assisted models to the best regular server predictions. To promote future progress in this category, we identify successes, challenges, and opportunities for improved strategies in prediction, assessment, and communication of SAXS data to predictors. An important observation is that, for many targets, SAXS data were inconsistent with crystal structures, suggesting that these proteins adopt different conformation(s) in solution. This CASP13 result, if representative of PDB structures and future CASP targets, may have substantive implications for the structure training databases used for machine learning, CASP, and use of prediction models for biology.