PLANET-MD: Ultra-fast Proteome-scale Prediction of Allosteric Networks in Proteins

Abstract

Proteins are dynamic molecules that depend on conformational flexibility to carry out functions in the cell, yet despite significant advances in the modeling of static protein structure, prediction of these dynamics remains challenging. We introduce PLANET-MD, a machine learning model that predicts dynamic protein properties from sequence or static structure with unprecedented speed and accuracy. Trained on thousands of molecular dynamics trajectories spanning diverse protein families, PLANET-MD simultaneously models multiple dynamics features: root-mean-square fluctuations (RMSF), generalized correlation coefficients (GCC-LMI), and a novel structural heterogeneity profile (SHP) based on recent structure quantization methods. PLANET-MD significantly outperforms existing methods in predicting simulation-derived dynamics. We reduce RMSF prediction error by 57% compared to BioEmu and calibrated Dyna-1 predictions, including an up to 73% error reduction for long proteins. We validate these predictions with experimental hetNOE data, and we demonstrate the ability to adapt predictions to different physical temperatures. We highlight PLANET-MDs utility in constructing allosteric networks in the oncogene KRAS and identify structural sub-modules with correlated motions, and we validate PLANET-MD by showing that changes in node centrality within predicted KRAS allosteric networks correlate with changes of folding free energy in experimental DMS data. Our approach makes predictions in seconds rather than hours or days, enabling us to perform the first comprehensive dynamics analysis of the entire human proteome. PLANET-MD bridges the gap between static structural biology and dynamic functional understanding, enabling dynamics-aware structural analysis and variant effect prediction at scales previously unavailable. PLANET-MD is available as free and open-source software at https://github.com/flatironinstitute/PLANET-MD.