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Characterizing the Effects of Sequence Variability in Molecular Function, Evolution and Design

Award Number: R35GM133631
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Characterizing the Effects of Sequence Variability in Molecular Function, Evolution and Design - Proposal Summary Biological sequences that perform a functional role evolve via changes that tend to preserve their original function or by the acquisition of new properties that might confer a fitness advantage. The processes that lead to novel functional sequences or those that explain a negative effect given a biomolecular change are not yet fully understood. Solving this puzzle is challenging given the complex network of interactions and constraints that biomolecules are subject during evolution. This MIRA project aims to continue our efforts to understand, characterize and utilize landscapes of sequence variability and the effect of sequence change on function and fitness of biomolecules. We have developed tools based on epistatic probabilistic models, latent generative models, and evolutionary dynamics to have a predictive understanding on how sequence composition as well as novel sequence space leads to biomolecules with certain functional properties and fitness. Over the past years we have made contributions and providing evidence that it is possible to construct coevolutionary models using extant sequence data that can infer if novel sequences will have certain functional properties or if the changes will be detrimental. In this project, we propose to continue developing techniques based on state-of-the-art computational techniques in machine learning that are aided by our interpretable epistatic models to 1) increase the accuracy of our sequence fitness landscape determination and navigate landscapes effectively, 2) be able to design and experimentally test novel biomolecules with desired functional properties, 3) understand the dynamics of functional preservation in pathogenic molecules that might aid the forecasting of variants that can contribute to disease or antibiotic resistance. This project will allow us to expand our developments of Latent Generative Landscapes (LGL) and models of sequence evolution with epistatic contributions (SEEC) to work with new and more complex systems as the ones we have worked in the past, including metal transporters, temperature sensing proteins, proteases, viral proteins, and antibiotic resistance enzymes. Our key hypothesis is that an accurate modeling of the latent manifold of the protein sequence space will lead us to a better inference of functional classification of many uncharacterized proteins, help us understand and fine-tune the most important determinants for functional selectivity and predict evolutionary trajectories of biomolecules that could then be used for therapeutic purposes like vaccine development and drug design.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $541,096 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	6	5/16/2025	COMPETING CONTINUATION	$541,096
2025	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	5	5/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $541,096

Issue Date FY: 2023 ( Subtotal = $394,100 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	5	8/23/2023	NON-COMPETING CONTINUATION	$380,216
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	4	6/22/2023	SUPPLEMENT FOR EXPANSION	$13,884
														Subtotal = $394,100

Issue Date FY: 2022 ( Subtotal = $380,216 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	4	8/2/2022	NON-COMPETING CONTINUATION	$380,216
														Subtotal = $380,216

Issue Date FY: 2021 ( Subtotal = $444,188 )
2021	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	3	8/23/2021	SUPPLEMENT FOR EXPANSION	$61,830
2021	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	3	8/4/2021	NON-COMPETING CONTINUATION	$382,358
														Subtotal = $444,188

Issue Date FY: 2020 ( Subtotal = $374,916 )
2020	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	2	7/28/2020	NON-COMPETING CONTINUATION	$374,916
														Subtotal = $374,916

Issue Date FY: 2019 ( Subtotal = $380,216 )
2019	2019	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	1	8/15/2019	NEW	$380,216
														Subtotal = $380,216

Grand Total All Awards = $2,514,732

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Characterizing the Effects of Sequence Variability in Molecular Function, Evolution and Design

Award Number: R35GM133631

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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