ÀÏ»¢»ú¹¥ÂÔ

Personal Summary

Hughes Lab News

11/24 is published. We are excited to be part of this project which aims to gather and store as much simulation data as possible for use in many fields, including building machine-learning models from molecular dynamics data for fast computation of the molecular structural ensemble.

10/24 Our newest publication!  shows the same ligands produce both biased signaling and cause a nuclear receptor to favor certain coactivators. We did a lot of work to rule out non-interesting sources of observed biased signaling in adipocytes.

8/24 Congratulations to Dr. Mariah Rayl on the successful defense of her dissertation!

7/07/24 The NIH funds a new ITC! We get to throw away the old one. Hooray!

5/24 Lydia Garrick's summer work on phase separation of transcription factors and cofactors is funded by the Center for Translational Medicine.

5/24 Welcome Bethany Miller! Bethany has joined the lab as a PSDD PhD student.

11/02/23 to 5/24 Travis visited the Universidad de Talca (Chile) to work with several groups at the Center for Bioinformatics, Simulations and Modelling () and attended  in early November.

07.26.23 Our 1-year pilot project is funded to study condensate formation by nuclear receptors and their cofactors. Congratulations Michelle Nemetchek who drove this application and will do most of the work.

07.22.23 We had our second successful computational biology workshop (CompBioAsia23), this time in Singapore at the National University of Singapore. Thanks to all who made it great! 

06.20.23 Congratulations to Mariah Rayl on receiving the Stella Duncan Fellowship that will support her salary for 1 year!

05.15.23 Congratulations to Connor Abel and Lydia Garrick on receiving Center for Translational Medicine summer undergraduate research fellowships 

12.19.22 Michelle Nemetchek successfully defended her PhD dissertation! Congrats Michelle!

12.10.22 Michelle Nemetchek is awarded a travel grant to the Biophysical Society meeting in San Diego.

12.05.22 Our paper is published in PNAS check it out: 

08.01.22 We have funding for the next five years to explore biased agonism in nuclear receptors! 

Dr. Hughes leads a group of 6 graduate students and post-docs along with several undergraduate and high-school students focused on understanding how drugs work using a variety of computational and experimental methods.  He has authored or co-authored 28 research manuscripts that have garnered over 3000 total citations.  Dr. Hughes earned Bachelor’s and Master’s degrees in physics and graduated from the University of Colorado with a Ph.D. in biology in 2008. He has since worked in the protein biophysics and biochemistry field including leading protein redesign efforts at a nascent biotech company in Spain, an NIH-supported fellowship in nuclear receptor biophysics in the lab of Dr. Douglas Kojetin at the Scripps Research Institute in Jupiter Florida, and training in molecular simulation in the lab of Dr. Thomas Cheatham III at the University of Utah. Current major funding for the Hughes lab comes from the National Institutes of Health which supports research in drug design and understanding how nuclear receptors signal at atomic resolution. Dr. Hughes is Co-PI with Dr. Amitava Roy on an National Science Foundation educational grant that supports two annual international computational biology workshops (compbioasia.org). 

Education

B.S. Physics, M.S. Physics, Ph.D. Molecular, Cellular and Developmental Biology

Courses Taught

Dr. Hughes and Dr. Amitava Roy are Co-PIs on an NSF grant that supports computational biology training: compbioasia.org. 

Classes I teach and/or coordinate:

PHAR 329 (Microbes and Medicines)

BCH 294 (Biochemistry Seminar: Intro to Biochemistry Faculty Research)

BMED 615 (Molecular Pharmacology)

Classes I teach for 2-3 weeks per course:

PHAR 362 (Pharmaceutical Sciences Lab II)

BCH 581 (Physical Biochemistry) I teach mainly about molecular dynamics

Research Interests

The Hughes lab does Drug Design in collaboration with medicinal chemists. We also study how drugs change the receptors they bind to using various biochemical and biophysical experimental methods along with molecular dynamics simulations. We connect these drug-induced biophysical changes with functional outcomes in cell culture (e.g. through measurement of transcription). Our primary methods are multidimensional protein NMR, fluorine NMR, computational simulations, isothermal titration calorimetry, time-resolved FRET, fluorescence polarization, cell culture, and transcriptome analysis. We focus on the nuclear hormone receptor family, which is the molecular target of more than 10% of FDA-approved drugs. Our work improves the biophysical understanding of how drugs produce effects in this family which aids the development of new therapies with reduced undesired effects. Current work mainly focuses on one member of this family, PPARγ, which binds the prescription anti-diabetes drugs pioglitazone (Actos) and rosiglitazone (Avandia). 

Lab Members

Postdocs:

Michelle Nemetchek uses protein crystallization, NMR, FRET, fluorescence polarization, and cell-based assays to investigate the structural basis of the anti-inflammatory properties of the nuclear receptor PPARγ. Michelle (who was a PhD student in the Hughes lab) contributed most of the functional data for the publication "". Michelle also contributed significantly to "". Michelle was the lead author of our recent paper in PNAS: .

Biochemistry and Biophysics Graduate Students:

Mariah Rayl is a 5th year Ph.D. student using Molecular simulations and RNAseq (including the cell culturing part!) to define the acute effects of PPARγ binding drugs on adipocytes and connect those effects to protein structural states.

Reece Lott (Biochemistry and Biophysics Ph.D. student) who started volunteering in the lab in January 2022 as un undergraduate. He is currently optimizing purification of FXR and understanding biased agonism.

Nicholas O'Connor (Biochemistry and Biophysics Ph.D. student). Nick joined the lab in April 2023 and is currently working on purification of coregulator intrinsically disordered regions and preparing samples using HDX-MS to understand biased agonism in PPARγ.

Pharmaceutical Sciences and Drug Design Graduate Students:

Andrew Voss first joined the lab doing research for credit as an undergraduate in Biochemistry. In the Spring of 2022 Andy started in the lab as a Pharmaceutical Sciences and Drug Design Graduate Student (Joint with Philippe Diaz lab). Andy is designing synthesizable small molecules that bind PPARγ and then using molecular dynamics to identify candidates with desired binding modes and then actually synthesizing promising candidates. Andy then plans on testing the effect of these ligands on the structural ensemble (i.e., shape and movement) of PPARγ and their effect on coregulator binding. 

Undergraduates and PharmD student volunteers:

Lydia Garrick is a Biochemistry undergraduate who has volunteered in the lab since Fall 2022 and is helping with coregulator IDR condensate/aggregate characterization and general protein purification.

Stefan Meinken and Connor Abel (PharmD students) started volunteering in the lab Spring 2023. They plan on pursuing a PharmD/MS and are purifying nuclear receptor coregulator receptor interaction domains from bacteria and investigating transcriptional control of a unique PPAR promoter in cells.

Lab Alumni:

Postdocs:

Dr. Zahra Heidari focused on the simulation of nuclear receptors using conventional molecular dynamics in combination with various enhanced sampling techniques including accelerated molecular dynamics. Dr. Heidari now works for a biotech company. Dr. Heidari came to the lab with experience in the development of analysis methods for molecular dynamics simulations (e.g. Using Wavelet Analysis To Assist in the Identification of Significant Events in Molecular Dynamics Simulations) and is contributed to multiple projects involving simulations. (2017-2020).

Undergraduates:

Keri Nauman, a Biochemistry student, joined the lab January 2018 and worked on protein purification and biochemical assays until Fall 2018. 

Graduate Students:

Ian Chrisman graduated with a PhD in December 2018. He used protein crystallization, NMR, FRET and fluorescence polarization to gather structural information about the ensemble of structures of the nuclear receptor PPARγ in distinct functional states (i.e. corepressor bound, coactivator bound etc.). Ian is currently a Scientist I at Salubris Biotherapeutics.

Trey Patton graduated with a Master's degree from the Pharmaceutical Sciences and Drug Design program in May 2019. He now is a Research Scientist at a contract research and manufacturing organization. He used simulation and chemical synthesis to rationally design PPARγ binding drugs. Dr. Philippe Diaz and Dr. Hughes jointly advised Trey.

Vikash Kumar graduated with a Master's degree from the Biochemistry and Biophysics program in May 2021. He currently teaches Chemistry in India.

PharmD Students:

Elliot Littman and Nina Borzoni (currently finishing their PharmD degrees)

Projects

Current Funding:

NIH NIDDK R01DK129646 (2022-2027) "Structural definition of biased agonism in the nuclear receptor PPAR gamma."

IRES Track II: Cross-disciplinary Computational Biology Training
(PI Amitava Roy; Co-PI, Travis Hughes and Travis Wheeler [University of Arizona])
NSF IRES Track II Adanced Studies Institute (2024-2027)

Past Funding:

NIH NIGMS Pilot Project (CoBRE Phase III, 2023-2024)

IRES Track II: Cross-disciplinary Computational Biology Training
NSF IRES Track II Adanced Studies Institute (2020-2024)

NIH NIGMS Junior Investigator Award (CoBRE Phase II: 2019-2022)

NIH NIGMS Pilot Project Award via the Center for Biomolecular Structure and Dynamics (CoBRE Phase II: 2018-2019)

NIH NIDDK Pathway to Independence Fellow (K99/R00: 2014-2018)

NIH (NIDDK) NRSA Fellowship (F32: 2012-2014) 

American Heart Association Post-doctoral Fellow (2012)

Selected Publications

Hughes lab members in bold. For a complete list of publications see:

Roy, A., Ward, E., Choi, I., Cosi, M., Edgin, T., Hughes, T. S., Islam, M. S., Khan, A. M., Kolekar, A., Rayl, M., Robinson, I., Sarando, P., Skidmore, E., Swetnam, T. L., Wall, M., Xu, Z., Yung, M. L., Merchant, N. & Wheeler, T. J. Nucleic Acids Res (2024) doi:10.1093/nar/gkae1109.

Rayl, M. L., Nemetchek, M. D., Voss, A. H. & Hughes, T. S. Mol Pharmacol 106, 309 (2024). PMID: 39443155 DOI: https://doi.org/10.1124/molpharm.124.000992

Burris, T. P., de Vera, I. M. S., Cote, I., Flaveny, C. A., Wanninayake, U. S., Chatterjee, A., Walker, J. K., Steinauer, N., Zhang, J., Coons, L. A., Korach, K. S., Cain, D. W., Hollenberg, A. N., Webb, P., Forrest, D., Jetten, A. M., Edwards, D. P., Grimm, S. L., Hartig, S.Lange CA, Richer JK, Sartorius CA, Tetel M, Billon C, Elgendy B, Hegazy L, Griffett K, Peinetti N, Burnstein KL, Hughes TS, Sitaula S, Stayrook KR, Culver A, Murray MH, Finck BN, Cidlowski JA. Pharmacol Rev. 2023 Nov;75(6):1233-1318. doi: 10.1124/pharmrev.121.000436. Epub 2023 Aug 16. Review. PubMed PMID: 37586884; PubMed Central PMCID: PMC10595025

Affiliations

Graduate Programs

Pharmaceutical Sciences and Drug Design

Neuroscience

Centers

Honors / Awards