Protein Dynamics Beyond Structure Prediction

The ability to predict protein three-dimensional structures from amino acid sequences is a landmark achievement in molecular biology, where recent deep learning approaches such as AlphaFold are the culmination of decades of work. Yet, the quantitative understanding of how protein sequences give rise to dynamic conformational changes and higher-order assemblies remains unsolved. Folding and conformational states are dynamic, stochastic processes, shaped by sequence, energy, co-translational constraints, chaperone machineries, and the physicochemical conditions of the cellular environment. Recent advances now position the field to move beyond static structural endpoints toward a mechanistic understanding of folding dynamics in living systems. Single-molecule techniques enable time-resolved observation of folding trajectories and intermediate states hitherto hidden by traditional structural biology approaches, while computational innovations and data-driven approaches offer new ways to integrate heterogeneous data across scales. In this Roadmap, we review the current conceptual landscape of protein folding, examine the experimental and theoretical gaps that remain, and discuss emerging strategies that integrate high-resolution measurements with multiscale modeling. We outline a roadmap toward a quantitative and predictive science of protein folding dynamics, conformational kinetics, and macromolecular self-assembly. Realizing this vision would transform our understanding of the dynamics of molecular self-organization, from the folding of individual polypeptides to the emergence of dynamic macromolecular complexes. This will enable rational control of folding and misfolding in health and disease, extend protein engineering principles beyond static structural design, and establish a mechanistic foundation for predictive and personalized interventions in proteostasis-related disorders.

Source: arXiv:2606.08647v1 - http://arxiv.org/abs/2606.08647v1 PDF: https://arxiv.org/pdf/2606.08647v1 Original Link: http://arxiv.org/abs/2606.08647v1