MELD-Adapt: On-the-Fly Belief Updating in Integrative Molecular Dynamics

Integrative structural biology synergizes experimental data with computational methods to elucidate the structures and interactions within biomolecules, a task that becomes critical in the absence of high-resolution structural data. A challenging step for integrating the data is knowing the expected accuracy or belief in the dataset. We previously showed that the Modeling Employing Limited Data (MELD) approach succeeds at predicting structures and finding the best interpretation of the data when the initial belief is equal to or slightly lower than the real value. However, the initial belief might be unknown to the user, as it depends on both the technique and the system of study. Here we introduce MELD-Adapt, designed to dynamically evaluate and infer the reliability of input data while at the same time finding the best interpretation of the data and the structures compatible with it. We demonstrate the utility of this method across different systems, particularly emphasizing its capability to correct initial assumptions and identify the correct fraction of data to produce reliable structural models. The approach is tested with two benchmark sets: the folding of 12 proteins with coarse physical insights and the binding of peptides with varying affinities to the extraterminal domain using chemical shift perturbation data. We find that subtle differences in data structure (e.g., locally clustered or globally distributed), starting belief, and force field preferences can have an impact on the predictions, limiting the possibility of a transferable protocol across all systems and data types. Nonetheless, we find a wide range of initial setup conditions that will lead to successful sampling and identification of native states, leading to a robust pipeline. Furthermore, disagreements about how much data is enforced and satisfied rapidly serve to identify incorrect setup conditions.