Deniz Aydin

All Publications

• CLoNe: automated clustering based on local density neighborhoods for application to biomolecular structural ensembles BIOINFORMATICS Trager, S., Tamo, G., Aydin, D., Fonti, G., Audagnotto, M., Dal Peraro, M. 2021; 37 (7): 921-928

  Abstract

  Proteins are intrinsically dynamic entities. Flexibility sampling methods, such as molecular dynamics or those arising from integrative modeling strategies, are now commonplace and enable the study of molecular conformational landscapes in many contexts. Resulting structural ensembles increase in size as technological and algorithmic advancements take place, making their analysis increasingly demanding. In this regard, cluster analysis remains a go-to approach for their classification. However, many state-of-the-art algorithms are restricted to specific cluster properties. Combined with tedious parameter fine-tuning, cluster analysis of protein structural ensembles suffers from the lack of a generally applicable and easy to use clustering scheme.We present CLoNe, an original Python-based clustering scheme that builds on the Density Peaks algorithm of Rodriguez and Laio. CLoNe relies on a probabilistic analysis of local density distributions derived from nearest neighbors to find relevant clusters regardless of cluster shape, size, distribution and amount. We show its capabilities on many toy datasets with properties otherwise dividing state-of-the-art approaches and improves on the original algorithm in key aspects. Applied to structural ensembles, CLoNe was able to extract meaningful conformations from membrane binding events and ligand-binding pocket opening as well as identify dominant dimerization motifs or inter-domain organization. CLoNe additionally saves clusters as individual trajectories for further analysis and provides scripts for automated use with molecular visualization software.www.epfl.ch/labs/lbm/resources, github.com/LBM-EPFL/CLoNe.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/btaa742

  View details for Web of Science ID 000654708400005

  View details for PubMedID 32821900

  View details for PubMedCentralID PMC8128458

• Delineating the Ligand-Receptor Interactions That Lead to Biased Signaling at the μ-Opioid Receptor. Journal of chemical information and modeling Kelly, B., Hollingsworth, S. A., Blakemore, D. C., Owen, R. M., Storer, R. I., Swain, N. A., Aydin, D., Torella, R., Warmus, J. S., Dror, R. O. 2021

  Abstract

  Biased agonists, which selectively stimulate certain signaling pathways controlled by a G protein-coupled receptor (GPCR), hold great promise as drugs that maximize efficacy while minimizing dangerous side effects. Biased agonists of the μ-opioid receptor (μOR) are of particular interest as a means to achieve analgesia through G protein signaling without dose-limiting side effects such as respiratory depression and constipation. Rational structure-based design of biased agonists remains highly challenging, however, because the ligand-mediated interactions that are key to activation of each signaling pathway remain unclear. We identify several compounds for which the R- and S-enantiomers have distinct bias profiles at the μOR. These compounds serve as excellent comparative tools to study bias because the identical physicochemical properties of enantiomer pairs ensure that differences in bias profiles are due to differences in interactions with the μOR binding pocket. Atomic-level simulations of compounds at μOR indicate that R- and S-enantiomers adopt different poses that form distinct interactions with the binding pocket. A handful of specific interactions with highly conserved binding pocket residues appear to be responsible for substantial differences in arrestin recruitment between enantiomers. Our results offer guidance for rational design of biased agonists at μOR and possibly at related GPCRs.

  View details for DOI 10.1021/acs.jcim.1c00585

  View details for PubMedID 34251810

• An Isoprene Lipid-Binding Protein Promotes Eukaryotic Coenzyme Q Biosynthesis MOLECULAR CELL Lohman, D. C., Aydin, D., Von Bank, H. C., Smith, R. W., Linke, V., Weisenhorn, E., McDevitt, M. T., Hutchins, P., Wilkerson, E. M., Wancewicz, B., Russell, J., Stefely, M. S., Beebe, E. T., Jochem, A., Coon, J. J., Bingman, C. A., Dal Peraro, M., Pagliarini, D. J. 2019; 73 (4): 763-+

  Abstract

  The biosynthesis of coenzyme Q presents a paradigm for how cells surmount hydrophobic barriers in lipid biology. In eukaryotes, CoQ precursors-among nature's most hydrophobic molecules-must somehow be presented to a series of enzymes peripherally associated with the mitochondrial inner membrane. Here, we reveal that this process relies on custom lipid-binding properties of COQ9. We show that COQ9 repurposes the bacterial TetR fold to bind aromatic isoprenes with high specificity, including CoQ intermediates that likely reside entirely within the bilayer. We reveal a process by which COQ9 associates with cardiolipin-rich membranes and warps the membrane surface to access this cargo. Finally, we identify a molecular interface between COQ9 and the hydroxylase COQ7, motivating a model whereby COQ9 presents intermediates directly to CoQ enzymes. Overall, our results provide a mechanism for how a lipid-binding protein might access, select, and deliver specific cargo from a membrane to promote biosynthesis.

  View details for DOI 10.1016/j.molcel.2018.11.033

  View details for Web of Science ID 000459253700012

  View details for PubMedID 30661980

  View details for PubMedCentralID PMC6386619

• Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family CELL CHEMICAL BIOLOGY Reidenbach, A. G., Kemmerer, Z. A., Aydin, D., Jochem, A., McDevitt, M. T., Hutchins, P. D., Stark, J. L., Stefely, J. A., Reddy, T., Hebert, A. S., Wilkerson, E. M., Johnson, I. E., Bingman, C. A., Markley, J. L., Coon, J. J., Dal Peraro, M., Pagliarini, D. J. 2018; 25 (2): 154-+

  Abstract

  Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here, we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates. We further create an analog-sensitive version of Coq8p and reveal that acute chemical inhibition of its endogenous activity in yeast is sufficient to cause respiratory deficiency concomitant with CoQ depletion. Collectively, this work defines lipid and small-molecule modulators of an ancient family of atypical kinase-like proteins and establishes a chemical genetic system for further exploring the mechanistic role of COQ8 in CoQ biosynthesis.

  View details for DOI 10.1016/j.chembiol.2017.11.001

  View details for Web of Science ID 000425281100007

  View details for PubMedID 29198567

  View details for PubMedCentralID PMC5819996

• Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity MOLECULAR CELL Stefely, J. A., Licitra, F., Laredj, L., Reidenbach, A. G., Kemmerer, Z. A., Grangeray, A., Jaeg-Ehret, T., Minogue, C. E., Ulbrich, A., Hutchins, P. D., Wilkerson, E. M., Ruan, Z., Aydin, D., Hebert, A. S., Guo, X., Freiberger, E. C., Reutenauer, L., Jochem, A., Chergova, M., Johnson, I. E., Lohman, D. C., Rush, M. P., Kwiecien, N. W., Singh, P. K., Schlagowski, A. I., Floyd, B. J., Forsman, U., Sindelar, P. J., Westphall, M. S., Pierrel, F., Zoll, J., Dal Peraro, M., Kannan, N., Bingman, C. A., Coon, J. J., Isope, P., Puccio, H., Pagliarini, D. J. 2016; 63 (4): 608–20

  Abstract

  The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.

  View details for DOI 10.1016/j.molcel.2016.06.030

  View details for Web of Science ID 000381620300009

  View details for PubMedID 27499294

  View details for PubMedCentralID PMC5012427