Decoding How Proteins Fold

One of the most puzzling and unsolved challenges in molecular biology is understanding how proteins fold. Despite having advanced predictive tools that can accurately estimate the native structures of proteins, we still lack a comprehensive model that explains how amino acid sequences dictate folding pathways and trajectories. This manuscript takes a fresh approach to this problem by resorting to the principle of least action. This approach enables us to explore an intriguing question: how does a protein achieve its native state at a constant folding rate and within a time frame that is biologically plausible? A response to this inquiry will help us understand why proteins must fold along specific pathways and identify the boundary conditions that restrict their availability. It will also clarify why different folding pathways could be characterized by a common effective folding trajectory. Finally, it will provide a clear explanation for Levinthal's paradox. Our results are expected to pave the way for a more profound understanding of how proteins fold, shedding light on how the amino acid sequence and its surrounding environment encode the protein's folding pathways and, consequently, the protein's three-dimensional structure.