Motivation After the outstanding breakthrough of AlphaFold in predicting protein 3D models, new questions appeared and remain unanswered. The ensemble nature of proteins, for example, challenges the structural prediction methods because the models should represent a set of conformers instead of single structures. The evolutionary and structural features captured by effective deep learning techniques may unveil the information to generate several diverse conformations from a single sequence. Here we address the performance of AlphaFold2 predictions obtained through ColabFold under this ensemble paradigm. Results Using a curated collection of apo-holo pairs of conformers, we found that AlphaFold2 predicts the holo form of a protein in ∼70% of the cases, being unable to reproduce the observed conformational diversity with the same error for both conformers. More importantly, we found that AlphaFold2's performance worsens with the increasing conformational diversity of the studied protein. This impairment is related to the heterogeneity in the degree of conformational diversity found between different members of the homologous family of the protein under study. Finally, we found that main-chain flexibility associated with apo-holo pairs of conformers negatively correlates with the predicted local model quality score plDDT, indicating that plDDT values in a single 3D model could be used to infer local conformational changes linked to ligand binding transitions. Availability Data and code used in this manuscript are publicly available at https://gitlab.com/sbgunq/publications/af2confdiv-oct2021 Supplementary Information Supplementary data is available at the journal's web site.
After the outstanding breakthrough of AlphaFold in predicting protein 3D models, new questions appeared and remain unanswered. The ensemble nature of proteins, for example, challenges the structural prediction methods because the models should represent a set of conformers instead of single structures. The evolutionary and structural features captured by effective deep learning techniques may unveil the information to generate several diverse conformations from a single sequence. Here we address the performance of AlphaFold2 predictions under this ensemble paradigm. Using a curated collection of apo-holo conformations, we found that AlphaFold2 predicts the holo form of a protein in 70% of the cases, being unable to reproduce the observed conformational diversity with an equivalent error than in the estimation of a single conformation. More importantly, we found that AlphaFold2’s performance worsens with the increasing conformational diversity of the studied protein. This impairment is related to the heterogeneity in the degree of conformational diversity found between different members of the homologous family of the protein under study. Finally, we found that main-chain flexibility associated with apo-holo pairs of conformers negatively correlates with the predicted local model quality score plDDT, indicating that plDDT values in a single 3D model could be used to infer local conformational changes linked to ligand binding transitions.
The emerging picture of protein nature reveals its intrinsic metastability. According to this idea, although a protein is kinetically trapped in a local free energy minimum that defines its native state, those kinetic barriers can be overcome by a complex mixture of the protein's intrinsic properties and environmental conditions, promoting access to more stable states such as the amyloid fibril. Proteins that are strongly driven towards aggregation in the form of these fibrils are called amyloidogenic. In this work we study the evolutionary rates of 81 human proteins for which an in vivo amyloid state is supported by experiment-based evidence. We found that these proteins evolve faster when compared with a large dataset of ~16,000 reference proteins from the human proteome. However, their evolutionary rates were indistinguishable from those of secreted proteins that are already known to evolve fast. After analyzing different parameters that correlate with evolutionary rates, we found that the evolutionary rates of amyloidogenic proteins could be modulated by factors associated with metastable transitions such as supersaturation and conformational diversity. Our results showcase the importance of protein metastability in evolutionary studies.
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