NLM DIR Seminar Schedule
UPCOMING SEMINARS
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Feb. 18, 2025 Samuel Lee
Efficient predictions of alternative protein conformations by AlphaFold2-based sequence association -
Feb. 25, 2025 Zhizheng Wang
GeneAgent: Self-verification Language Agent for Gene Set Analysis using Domain Databases -
March 4, 2025 Sofya Garushyants
TBD -
March 11, 2025 Sanasar Babajanyan
TBD -
March 18, 2025 MG Hirsch
TBD
RECENT SEMINARS
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Feb. 11, 2025 Po-Ting Lai
Enhancing Biomedical Relation Extraction with Directionality -
Feb. 4, 2025 Victor Tobiasson
On the dominance of Asgard contributions to Eukaryogenesis -
Jan. 28, 2025 Kaleb Abram
Leveraging metagenomics to investigate the co-occurrence of virome and defensome elements at large scale -
Jan. 21, 2025 Qiao Jin
Artificial Intelligence for Evidence-based Medicine -
Jan. 17, 2025 Xuegong Zhang
Using Large Cellular Models to Understand Cell Transcriptomics Language
Scheduled Seminars on March 28, 2024
Contact NLMDIRSeminarScheduling@mail.nih.gov with questions about this seminar.
Abstract:
Although most globular proteins fold into a single stable structure, an increasing number have been shown to remodel their secondary and tertiary structures in response to cellular stimuli. State-of-the-art algorithms predict that these fold-switching proteins adopt only one stable structure, missing their functionally critical alternative folds. Why these algorithms predict a single fold is unclear, but all of them infer protein structure from coevolved amino acid pairs. Here, we hypothesize that coevolutionary signatures are being missed. Suspecting that single-fold variants could be masking these signatures, we developed an approach, called Alternative Contact Enhancement (ACE), to search both highly diverse protein superfamilies-composed of single-fold and fold-switching variants–and protein subfamilies with more fold-switching variants. ACE successfully revealed coevolution of amino acid pairs uniquely corresponding to both conformations of 56/56 fold-switching proteins from distinct families. Then, we used ACE-derived contacts to (1) predict two experimentally consistent conformations of a candidate protein with unsolved structure and (2) develop a blind prediction pipeline for fold-switching proteins. The discovery of widespread dual-fold coevolution indicates that fold-switching sequences have been preserved by natural selection, implying that their functionalities provide evolutionary advantage and paving the way for predictions of diverse protein structures from single sequences.