Document Type
Article
Author ORCID Identifier
Andrey O. Demkiv https://orcid.org/0000-0002-4976-3506
Saacnicteh Toledo‐Patiño https://orcid.org/0000-0003-0632-0075
Encarnación Medina‐Carmona https://orcid.org/0000-0001-5600-7648
Andrej Berg https://orcid.org/0000-0002-5232-1995
Gaspar Pinto https://orcid.org/0000-0002-8917-1169
Antonietta Parracino https://orcid.org/0000-0001-7259-1661
José M. Sánchez‐Ruiz https://orcid.org/0000-0002-9056-3928
Alvan C. Hengge https://orcid.org/0000-0002-5696-2087
Paola Laurino https://orcid.org/0000-0002-3725-2645
Liam M. Longo https://orcid.org/0000-0002-1773-0611
Shina Caroline Lynn Kamerlin https://orcid.org/0000-0002-3190-1173
Journal/Book Title
Molecular Biology and Evolution
Publication Date
3-12-2025
Publisher
Oxford University Press
Journal Article Version
Version of Record
Volume
42
Issue
4
First Page
1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Last Page
12
Abstract
At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this six to eight residue motif could have sparked the emergence of the very first nucleoside triphosphatases—a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected. Simulations suggest that phosphate binding is nonspecific, with a preference for GTP over orthophosphate. Control peptides with the same amino acid composition but different sequences and situated conformations behaved similarly to the Walker A peptides, revealing no indication that the Walker A sequence is privileged as a disembodied peptide. We conclude that the evolutionary history of the P-loop NTPase family is unlikely to have started with a disembodied Walker A peptide in an aqueous environment. The limits of evolutionary continuity for this protein family must be reconsidered. Finally, we argue that motifs such as the Walker A motif may represent incomplete or fragmentary molecular fossils—the true nature of which has been eroded by time.
Recommended Citation
Andrey O Demkiv, Saacnicteh Toledo-Patiño, Encarnación Medina-Carmona, Andrej Berg, Gaspar P Pinto, Antonietta Parracino, Jose M Sanchez-Ruiz, Alvan C Hengge, Paola Laurino, Liam M Longo, Shina Caroline Lynn Kamerlin, Redefining the Limits of Functional Continuity in the Early Evolution of P-Loop NTPases, Molecular Biology and Evolution, Volume 42, Issue 4, April 2025, msaf055, https://doi.org/10.1093/molbev/msaf055