Evolutionary Biophysics
Interface of biophysics and molecular evolution
The evolutionary forces of mutation, drift, and selection shape the variation in sequence, structure, and properties of biological molecules such as proteins and RNA/DNA. This has been traditionally the realm of evolutionary biology and population genetics, in particular molecular evolution. However, this variation is also shaped by constrains imposed by physics and chemistry on the molecule, traditionally the field of biophysics. We are interested in integrating the insights and experimental and theoretical approaches from protein folding and engineering to understand the genomic signatures of adaptive evolution and develop methodologies in phylogenetics.
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Interface of biophysics and microbial evolution
We are interested in understanding fundamental problems in the interface of protein biophysics and microbial evolution. Evolution and the physical properties of the target protein shape the trajectory to adaptation, however, very few groups combine these two disciplines, thus fundamental questions at the interface remain unsolved: What is the quantitative relationship between the biophysical properties of the target gene, selection regimes (e.g., drug dosage, cycle of drug administration, and combination of drugs), and demography (e.g., population size of microbes)? How does this relationship, together with stochasticity and contingency, determine the arising evolutionary pathways? We address these questions using a combination of theoretical and experimental techniques from biophysics and laboratory evolution. Our current projects involve the norovirus and E. coli.
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Biophysics
Transmembrane proteins
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) ion channel that regulates salt secretion and reabsorption in epithelial cells. Mutations in the cftr gene cause cystic fibrosis (CF). In 90% of CF patients, the disease-associated mutation is the deletion of phenylalanine 508 (Phe508), which is hypothesized to cause CFTR misassembly and misfolding. To understand the molecular defect of the CFTR misassembly due to Phe508 deletion, we used computational structural biology tools to develop a theoretical structural model of the CFTR channel.
Collaborators: Nikolay Dokholyan (UNC Biophysics), John Riordan (UNC Biochemistry & Cystic Fibrosis Center) |
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Protein engineering & drug discovery
We were also engaged in experimental and computational aspects of protein engineering and drug discovery. We developed a 3D structural model of the mu-opioid G-protein coupled receptor (mu-GPCR) and performed drug screening for new opioids. The screening led to the discovery of compounds with micromolar affinities that are now in the pipeline for further drug optimization. Additionally, using approaches in protein engineering, I designed cyclic peptide-based fluorescent ligand for the cysteine-rich intestinal protein 1 (CRIP1), a protein that is overexpressed during the early stages of breast cancer.
Collaborators: Nikolay Dokholyan (UNC) , Diatchenko Lab (McGill U) |
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Molecular motors
Dynein is a cytoskeletal motor protein that drives the beating of cilia and flagella and the minus-directed transport of molecules and organelles along the microtubule. We combine computational structural biology, molecular dynamics,and mathematical modeling to understand dynein structure and mechanism.
Collaborators: Nikolay Dokholyan (UNC Biophysics), Elston Lab (UNC Pharmacology); Denis Tsyganokov (Georgia Tech & Emory U) |
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