From sequence to protein structure and conformational dynamics with AI/ML

Abstract: The 2024 Nobel Prize in Chemistry was awarded in part for protein structure prediction using AlphaFold2, an artificial intelligence/machine learning (AI/ML) model trained on vast amounts of sequence and 3D structure data. AlphaFold2 and related models, including RoseTTAFold and ESMFold, employ specialized neural network architectures driven by attention mechanisms to infer relationships between sequence and structure. At a fundamental level, these AI/ML models operate on the long-standing hypothesis that the structure of a protein is determined by its amino acid sequence. More recently, AlphaFold2 has been adapted for the prediction of multiple protein conformations by subsampling multiple sequence alignments (MSAs). The deterministic relationship between sequence and structure was hypothesized over half a century ago with profound implications for the biological sciences ever since. Based on this relationship, we hypothesize that protein conformational dynamics are also determined, at least in part, by amino acid sequence and that this relationship may be leveraged for construction of AI/ML models dedicated to predicting ensembles of protein structures (i.e., distinct conformations). Accordingly, we conceptualized an AI/ML model architecture which may be trained on sequence data in combination with conformationally-sensitive structure data, coming primarily from nuclear magnetic resonance (NMR) spectroscopy. Sequence-informed prediction of protein structural dynamics has the potential to emerge as a transformative capability across the biological sciences, and its implementation could very well be on the horizon.