Federico Caamaño | Searcharxiv

arXiv2026

Dark energy: the cost of function in protein evolution

The evolutionary fate of proteins is driven by both folding stability and biological function, dual constraints that often conflict, creating frustration and imposing functional costs beyond stability. These costs can be captured by a "dark energy": the difference between the evolutionary energy of protein sequences and their physical folding energy. Recent advances in deep mutational scanning, protein language models, and inverse-folding models have enabled the quantification of dark energy across the protein universe. We review the computational and experimental approaches that disentangle folding and function at scale, revealing a dark energy component and providing new insights into how biological information flows from sequence to structure to function and back to sequence.

q-bio.BM↗

arXiv2025

Predicting protein folding dynamics using sequence information

Natural protein sequences somehow encode the structural forms that these molecules adopt. Recent developments in structure-prediction are agnostic to the mechanisms by which proteins fold and represent them as static objects. However, the amino acid sequences also encode information about how the folding process can happen, and how variations in the sequences impact on the populations of the distinct structural forms that proteins acquire. Here we present a method to infer protein folding dynamics based only on sequence information. For this, we will rely first on the obtention of a precise 'evolutionary field' from the observed variations in the sequences of homologous proteins. We then show how to map the energetics to a coarse-grained folding model where the protein is treated as a string of foldons that interact. We then describe how, for any given protein sequence of a family, the equilibrium folding curve can be computed and how the emergence of protein folding sub-domains can be identified. We finally present protocols to analyze how mutations perturb both the folding stability and the cooperativity, that represent predictions for a deep-mutational scan of a protein of interest.

q-bio.BM↗