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Dr. Ivet Bahar
Distinguished Professor & JK Vries Chair
Computational & Systems Biology Dept
School of Medicine, University of Pittsburgh
Associate Director, UP Drug Discovery Institute

"Bridging Structure & Function, via Dynamics"

In the News...

What we do and why:

The dynamics of living systems at the molecular level defines cell survival and regulation mechanisms, which in turn, define our physiological responses. Biomolecules work together in the cell in a seamless way: they communicate (intra- and intermolecular signaling), interact with each other (chemical reactions, binding, complex formation, assembly), produce and consume energy (mitochondrial functions, metabolic events), carry cargos (ion or substrate transport). They not only sustain and regulate cell life (transcription, translation, repair), but also orderly terminate it (apoptosis). How do biomolecules achieve so many functions? Because they have flexible structures that can adapt to changes and act in specific ways (intrinsic dynamics) driven by internal or external effects, controlled by principles of physical sciences and engineering, much like synthetic materials or machines. Chemical and physical rules that apply at the microscopic scale are not any different from those of the macroscopic world. Our goal is to help improve our understanding of the basic principles of biomolecular actions with the help of computing technology, visualize/simulate their time evolution, and discover rational intervention methods to counter their dysfunction.

Student Spotlight Heading Recent Publications image Research Progress Heading

Dr. Luca Ponzoni received the “Best Postdoc Award at the Department of Computational & Systems Biology – Year 2018” at the Annual Departmental Retreat in recognition of his outstanding work on the evaluation of the functional impact of missense variants (see Ponzoni & Bahar, Proc Natl Acad Sci USA 2018)

She (John) Zhang has been selected to represent Pitt's graduate students during the 2018 Pitt Day in Harrisburg, PA. She will present a poster (pictured below) to state lawmakers.


She (John) Zhang has received the Best DCSB Student Award for 2017, for his structure-based study of chromosomal dynamics using elastic network models. Below is a photo during his speech, after receiving the award, at the annual CSB Retreat Banquet.


Cihan received the Best DCSB Student Award for 2016 for his work on developing multi-scale models and simulations for dopaminergic signaling. He aims at understanding the effect of spatial complexity and heterogeneity in the efficiency of dopamine (DA) reuptake. Below is a snapshot from his simulations, displaying the release of DA (red dots) from active zones on DA neurons (green).


John received the best poster award in the DCSB retreat in June 2016 for his work on the ENM analysis of chromosome contact maps determined by Hi-C experiment.


Hongchun received the Best DCSB Postdoc Award for 2016 for developing the iGNM database and oGNM server, published in Nucleic Acids Research. The upgraded iGNM 2.0 database provides a user-friendly interface for retrieving information on the dynamics of 95% of Protein Data Bank (PDB) structures as well as their biological assemblies. It helps assess which structural elements undergo large correlated fluctuations, and enable conformational changes that may be relevant to function.



Publications 2019

Shared signature dynamics tempered by local fluctuations enables fold adaptability and specificity. (Mol Biol Evol 2019). Many families of proteins have been discovered to share similar folds but not necessarily similar sequences. It is of great interest to understand their evolutionarily conserved dynamical features as well as structural variations that contribute to their functional specificities. In this study, we performed a systematic computational analysis of 26,899 proteins belonging to 116 CATH super-families and examined the mode spectra of different protein super families by separate modes of motions into different frequency regimes.

Dr Ivet Bahar and co-authors Robert Jernigan and Ken Dill published a book, Protein Actions, with Garland Science.

Protein Actions

Improved pathogenicity prediction of missense variants based on structural dynamics considerations (PNAS 2018). We demonstrated that the analysis of a protein’s intrinsic dynamics can be successfully used to improve the prediction of the effect of point mutations on a protein functionality. This method employs ANM/GNM tools implemented in the ProDy Python package, in conjunction with other well-established predictors based on amino acid conservation and structural properties of the mutation site (e.g. solvent-accessible surface area).

Anion conductance mechanism (eLife 2017) of excitatory amino acid transporters (EAATs). We identified an intermediate anion channeling state (iChS) during the global transition from the outward facing (OF) to inward facing state (IFS). Our prediction was tested and validated by experimental study of critical residues and interactions by SCAM, electrophysiology and substrate uptake experiments (Amara lab; NIH).

DynOmics: dynamics of structural proteome and beyond. (Nucleic Acids Res. 2017)The portal is a newly developed server, ENM 1.0, which permits users to efficiently generate information on the collective dynamics of any structure in the presence of external environment, from lipid bilayer and crystal contacts, to substrate or ligands bound to a protein, or surrounding subunits in a multimeric structure or assembly.

Comparative analysis of AMPAR and NMDAR dynamics reveals striking similiarities, opening the way to designing new modulators of allosteric interactions.



Trimerization of dopamine transporter triggered by AIM-100 binding The Bahar (TR&D1) and Sorkin (DBP3) labs explored the trimerization of dopamine transporter (DAT) triggered by a furopyrimidine, AIM-100, using a combination of computational and biochemical methods, and single-molecule live-cell imaging assays. The study suggests the possibility of controlling dopamine transport upon altering the oligomerization state of DAT by small molecular binding, as a possible intervention strategy to modulate dopaminergic signaling.

Druggability Simulations and X-ray Crystallography Reveal a Ligand-binding Site in the GluA3 AMPA Receptor N-terminal Domain. We assessed the druggability of the ionotropic glutamate receptor subfamilies, using molecular dynamics simulations in the presence of drug-like molecules and new crystal structures. The study presents a novel ligand-binding site in the GluA3 N-terminal domain and provides pharmacophore features.

"Systems-level modeling identified a core network that enables cells to 'assess' cellular damage and make a 'life' or 'death' decision upon activating autophagy or apoptosis., in collaboration with the Perlmutter lab. Cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses through multiple feedback and feedforward loops. The proposed model also provides an in silico platform for developing pharmacological strategies for modulating cell decisions. "

"Allosteric modulation of intact γ-secretase structural dynamics", in collaboration with the Xie lab.
We analyzed the conformational dynamics of γ-secretase in the presence of lipid bilayer using an extension of the anisotropic network model (ANM) that takes account of lipid remodeling. The catalytic and allosteric site were identified using druggability simulations. A mechanic model was proposed to describe peptide binding, repositioning, cleavage and release.

"Connecting neuronal cell protective pathways and drug combinations in a Huntington's Disease model." We implementedQuantitative Systems Pharmacology(QSP) approach to gain a comprehensive, unbiased understanding of Huntington's disease processes to inform effective therapeutic strategies.

Structural dynamics, including allosteric switches, are evolutionarily maintained to accomplish biological activities, consistent with the paradigm sequence -> structure -> dynamics -> function where 'dynamics' bridges structure and function.


"Adaptability of protein structures to enable functional interactions and evolutionary implications " Turkan Haliloglu and Ivet BaharCurrent Opinion in Structural BIology (2015) 3517-23.

Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter. Using quantitative live-cell fluorescence microscopy (Sorkin lab) and molecular modeling (Bahar lab), we investigated the effects of the dopamine transporter (DAT) inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two DAT mutants.

"IFNα2, a Type-I interferon, forms a ternary complex with two receptors, IFNAR1 and IFNAR2. The binding affinity of IFNα2 to these receptors, as well as downstream signaling strength, can be modulated by altering the dynamics of the IFNAR1. IFNα2 associated immune responses were shown to be modulated by introducing Cys-Cys double mutants which form cross-links between different subdomains of IFNAR1. This was a collaborative study with the Schreiber lab at the Weizmann Institute in Israel where experiments (binding and functional assays) have been performed."