SPINDLE: Unlocking protein dynamics from single-field NMR relaxation data using a deep learning ensemble.

Abstract

A proteins function is derived from its three-dimensional structure and the motions of the atoms about that structure. The detailed characterization of both macromolecular structure and dynamics provides an opportunity for understanding enzyme catalysis, ligand binding, and allostery, along with providing insights into how the function changes upon mutation or post-translational modification. Among the various methods for characterizing biomolecular motions, nuclear magnetic resonance (NMR) spin relaxation methods are a standard for determining nanosecond global tumbling times along with the amplitude and timescale of faster local motions. Within the model-free formalism, various mathematical models are used to extract dynamic parameters. Unfortunately, as the number of fitted parameters increases within these models, they become mathematically underdetermined for standard NMR relaxation data collected at a single magnetic field, necessitating multi-field datasets. Here, we present SPINDLE, an ensemble of deep neural networks trained on a large synthetic set of NMR relaxation data. Unlike traditional least-squares fitting, SPINDLE predicts both fast and slow timescale dynamics parameters from a single set (i.e., collected at a single magnetic field) of three relaxation datasets using the ensemble for error estimation. We demonstrate a strong correlation to ground truth dynamics parameters on synthetic benchmarks, with more precision than traditional fitting techniques, and precisely reproduce experimental dynamics parameters for [~]50 proteins with relaxation data in the Biological Magnetic Resonance Data Bank. We also leverage the architecture of the deep neural network to show how the model emphasizes rigid residues for the prediction of global correlation times. This strategy may be useful in the future for elucidating correlated networks of dynamic residues from multiple relaxation datasets.