About

Abhinav Nath is an Associate Professor in Medicinal Chemistry at the University of Washington. His research focuses on understanding the relationship between protein dynamics and their normal functions or pathological dysfunctions. His lab investigates how conformational fluctuations in proteins are fundamental to processes such as enzyme catalysis, drug transport, motor protein function, and signal transduction. A significant aspect of his work involves studying proteins that are highly dynamic and do not fold into a single well-defined state, which presents challenges to conventional structural biology and drug design approaches. His research employs a broad range of experimental and theoretical methods from biochemistry, biophysics, and pharmacology. Notably, his lab utilizes single-molecule fluorescence spectroscopy and computational simulations to study systems such as the Glutathione-S-Transferase enzyme superfamily, involved in drug metabolism and oxidative stress response, and the intrinsically disordered protein Tau, which is implicated in Alzheimer’s disease and traumatic brain injury pathology. His work aims to develop new tools to study and modulate conformational fluctuations that are relevant to protein function and disease.

Research topics

• Biology
• Biophysics
• Chemistry
• Biochemistry
• Microbiology
• Computational biology
• Genetics
• Medicine
• Physics
• Cell biology

Selected publications

• Kinetics of cortisol and cortisone binding to corticosteroid binding globulin and albumin <i>in vivo</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17

  articleOpen access

  Abstract Cortisol is a major endogenous glucocorticoid that regulates numerous physiological processes. In plasma, cortisol and its inactive metabolite cortisone bind to corticosteroid-binding globulin (CBG) and albumin, leaving only the unbound fraction available for receptor activation and metabolism. Changes in ligand or protein concentrations alter unbound fractions. Existing binding equations are difficult to extend to multi-ligand, multi-protein systems and do not readily capture competitive endogenous binding interactions. The goal of this study was to develop a plasma protein binding model that quantitatively describes binding species and predicts unbound concentrations across physiological states. Total and unbound cortisol and cortisone, CBG and albumin were measured in plasma from healthy premenopausal women (n=13) at baseline and after 7 days of 30 mg hydrocortisone treatment. Reversible 1:1 binding models were implemented in COPASI and MATLAB/Simulink, and dissociation constants (K d ) were estimated by fitting binding models to observed unbound concentrations. A model describing simultaneous binding of cortisol and cortisone to CBG and albumin yielded in vivo K d values for cortisol:CBG, cortisone:CBG, cortisol:albumin, and cortisone:albumin of 0.0130 µM, 0.169 µM, 172 µM, and 519 µM, respectively. Model predictions agreed with observed unbound cortisol and cortisone, and bootstrap resampling confirmed stable K d estimates. This work provides a quantitative framework for predicting unbound cortisol and cortisone across physiological and disease states by accounting for both changes in ligand and protein concentrations. This enables extrapolation without reparameterization and supports exploration of conditions such as pregnancy, adrenal insufficiency, and liver disease, informing interpretation of altered cortisol concentrations in these populations. Significance statement This work establishes a framework to predict in vivo cortisol and cortisone binding. The developed model was applied to predict unbound cortisol and cortisone concentrations in physiological and pathophysiological states and can be integrated into pharmacokinetic models. Our analysis demonstrates that cortisol and cortisone binding affinities estimated in the native plasma environment differ from those measured using purified proteins. These differences have important implications for predicting and analyzing unbound cortisol concentrations. Graphical Abstract Created in BioRender. Authement, A. (2026) https://BioRender.com/zl1bg0k

  PublisherOA PDFDOI

• Function within Disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-29

  articleOpen accessCorresponding

  Abstract In numerous neurodegenerative diseases known collectively as tauopathies, the microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Tauopathies represent a substantial fraction of diseases associated with protein misfolding. Cellular chaperones known as small heat shock proteins (sHSPs) play a critical role in maintaining protein homeostasis by delaying the onset of protein aggregation. Two sHSPs, HSPB1 (Hsp27) and HSPB5 ( α B-crystallin), are constitutively expressed in brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity towards tau when activated by stress conditions such as pH acidosis. Using chimeric HSPB1/HSPB5 constructs in which small NTR subregions are swapped, we identify functional regions within the NTRs that modulate chaperone function for tau. The functional regions contain known sites of phosphorylation, suggesting that they are also control points that respond to cellular stress conditions. Our findings support an emerging model in which specific functional motifs within disordered regions of sHSPs govern activity and client engagement under normal and stress conditions. Broader Audience In many neurodegenerative diseases, the microtubule-associated protein tau forms fibrillar aggregates in the brain. Small heat shock proteins (sHSP) help prevent such aggregation, but their mechanisms of action remain enigmatic. We show HSPB1 and HSBP5, two sHSPs that are abundant and co-localize with tau, delay the onset of tau aggregation through distinct mechanisms. Each relies on specific small regions within their disordered N- terminal domains whose accessibility can be regulated by stress conditions and post- translational modifications.

  PublisherOA PDFDOI

• Rigorous Analysis of Multimodal HDX-MS Spectra

  Journal of the American Society for Mass Spectrometry · 2025-01-21 · 20 citations

  article

  An inherent strength of hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) is its ability to detect the presence of multiple conformational states of a protein, which often manifest as multimodal isotopic envelopes. However, the statistical considerations for accurate analysis of multimodal spectra have yet to be established. Here we outline an unrestrained binomial distribution fitting approach with the corresponding statistical tests to accurately detect and, when possible, deconvolute isotopic distributions that contain multiple subpopulations. The algorithms have been incorporated into an updated version of the freely available software, HX-Express, and validated using known mixtures of peptides deuterated to varying degrees. This approach presents a readily accessible tool to fit and interpret bimodal and trimodal behavior in HDX-MS data for mixed populations, EX1 kinetics, and pulse labeling data.

  PublisherDOI

• Tau4RD fibril polymorphism is imprinted during early aggregation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14

  preprintOpen accessSenior authorCorresponding

  Abstract Microtubule-associated protein tau forms characteristic fibrillar species in many neurodegenerative diseases. Neurofibrillary tangles, tau deposits observed in Alzheimer’s disease (AD), contain a mixture of amyloid-type polymorphic fibrils called paired helical filaments (PHFs) and straight filaments. The formation of heterogenous fibril populations is observed in other diseases and when tau aggregation is induced in vitro with polyanionic species. This suggests that tau’s structural transition from a conformational ensemble to various amyloid morphologies is a controlled and, therefore, controllable process. Despite many years of work toward describing aggregation intermediates that could address open questions such as whether fibril polymorphism is imprinted at the start of aggregation or arises due to conformational conversions, our understanding of amyloid structure remains predominantly based on observations of mature fibrils. It is unclear whether these processes are mutually exclusive and to what extent we can bias intermediate conformations toward less toxic states. Here to address the challenge of studying aggregation intermediates and tau’s structural conversion, we apply pulsed hydrogen-deuterium exchange with mass spectrometry (pulsed HDX-MS), which revealed differences in the subpopulations formed by tau4RD (a truncated tau construct) within seconds of initiating aggregation with polyphosphate and within hours of heparin-induction. This work begins to address the gap in knowledge regarding whether amyloid polymorphism is directly imprinted during nucleation or results from structural rearrangement during later stages of aggregation.

  PublisherOA PDFDOI

• Under the microscope: A structural and mechanistic examination of novel tau-targeted small-molecule aggregation inhibitors

  Biophysical Journal · 2024-02-01

  articleSenior author
  PublisherDOI

• Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

  eLife · 2024-07-26 · 1 citations

  preprintOpen accessSenior author

  Abstract Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer’s disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable “druggable” pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ∼100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.

  PublisherDOI

• Investigating the association between CYP2J2 inhibitors and QT prolongation: a literature review

  Drug Metabolism Reviews · 2024-03-13 · 2 citations

  review

  Drug withdrawal post-marketing due to cardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity is through inhibition of cardiac ion channels, leading to prolongation of the QT interval and sometimes fatal arrythmias. Recently, oxylipin signaling compounds have been shown to bind to and alter ion channel function, and disruption in their cardiac levels may contribute to QT prolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes, where it oxidizes arachidonic acid to cardioprotective epoxyeicosatrienoic acids (EETs). In addition to roles in vasodilation and angiogenesis, EETs bind to and activate various ion channels. CYP2J2 inhibition can lower EET levels and decrease their ability to preserve cardiac rhythm. In this review, we investigated the ability of known CYP inhibitors to cause QT prolongation using Certara's Drug Interaction Database. We discovered that among the multiple CYP isozymes, CYP2J2 inhibitors were more likely to also be QT-prolonging drugs (by approximately 2-fold). We explored potential binding interactions between these inhibitors and CYP2J2 using molecular docking and identified four amino acid residues (Phe61, Ala223, Asn231, and Leu402) predicted to interact with QT-prolonging drugs. The four residues are located near the opening of egress channel 2, highlighting the potential importance of this channel in CYP2J2 binding and inhibition. These findings suggest that if a drug inhibits CYP2J2 and interacts with one of these four residues, then it may have a higher risk of QT prolongation and more preclinical studies are warranted to assess cardiovascular safety.

  PublisherDOI

• Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein 1 (FABP1) and FABP1 Binding Alters Drug Metabolism

  Molecular Pharmacology · 2024-04-05 · 8 citations

  articleOpen access

  Liver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and up to two fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses, native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1, and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (K_d,1=0.2 µM) and low affinity (K_d,2&gt;10 µM) binding sites. Nine drugs bound to hFABP1 with K_d values ranging from 1 to 20 µM. None of the tested drugs completely displaced DAUDA from hFABP1 and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The k_cat of diclofenac hydroxylation by CYP2C9 was decreased by ~50% (p&lt;0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance. <b>Significance Statement</b> Many commonly prescribed drugs bind FABP1 forming ternary complexes with FABP1 and the fluorescent fatty acid DAUDA. These findings suggests that drugs will bind to apo-FABP1 and fatty acid bound FABP1 in the human liver. The high expression of FABP1 in the liver, together with drug binding to FABP1 may alter drug disposition processes <i>in vivo</i>.

  PublisherOA PDFDOI

• Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

  eLife · 2024-07-26

  preprintOpen accessSenior author

  Abstract Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer’s disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable “druggable” pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ∼100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.

  PublisherOA PDFDOI

• Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-02-03

  preprintOpen accessSenior authorCorresponding

  Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer's disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable "druggable" pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ~100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.

  PublisherOA PDFDOI

Recent grants

• Neuropathogenesis of Retroviral Infections

  NIH · $73.7M

Frequent coauthors

• Miklós Guttman

  University of Washington

  40 shared

• Ellie I. James

  University of Washington

  35 shared

• Elizabeth Rhoades

  University of Pennsylvania

  30 shared

• David W. Baggett

  University of Washington

  29 shared

• Thomas Nixey

  Takeda (United States)

  25 shared

• Joel B. Schachter

  Takeda (United States)

  25 shared

• Edcon Chang

  Takeda (United States)

  25 shared

• Karoline Choi

  St. Jude Children's Research Hospital

  25 shared

Education

• Ph.D., Medicinal Chemistry; Biomolecular Structure & Design

  University of Washington

  2008

• B.A., Biology; Chemistry

  University of Virginia

  2003