Browsing by Author "Doruker, Pemra"

Now showing 1 - 11 of 11

Citation Count: 0
Beta-2 adrenerjik reseptör proteinin dinamik yapısının araştırılması ve bilgisayar destekli ilaç tasarımındaki önemi
(2012) Akdoğan, Ebru Demet; Doruker, Pemra
[Abstract Not Available]
Citation Count: 12
Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from Trypanosoma cruzi and Human
(Wiley-VCH Verlag GmbH, 2011) Kurkcuoglu, Zeynep; Ural, Gulgun; Akten, Ebru Demet; Doruker, Pemra
We aim to uncover the binding modes of benzothiazoles which have been reported as specific inhibitors of triosephosphate isomerase from the parasite Trypanosoma cruzi (TcTIM) by performing blind dockings on both TcTIM and human TIM (hTIM). Detailed analysis of binding sites and specific interactions are carried out based on ensemble dockings to multiple receptor conformers obtained from molecular dynamics simulations. In TcTIM dimer dockings the inhibitors preferentially bind to the tunnel-shaped cavity formed at the interface of the subunits whereas non-inhibitors mostly choose other sites. In contrast TcTIM monomer binding interface and hTIM dimer interface do not present a specific binding site for the inhibitors. These findings point to the importance of the tunnel and of the dimeric form for inhibition of TcTIM. Specific interactions of the inhibitors and their sulfonate-free derivatives with the receptor residues indicate the significance of sulfonate group for binding affinity and positioning on the TcTIM dimer interface. One of the inhibitors also binds to the active site which may explain its relatively higher inhibition effect on hTIM.
Citation Count: 39
A Docking Study Using Atomistic Conformers Generated via Elastic Network Model for Cyclosporin A/Cyclophilin A Complex
(Taylor & Francis Inc, 2009) Akten, Ebru Demet; Cansu, Sertan; Doruker, Pemra
Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest-frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet Surprisingly the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also the small backbone variations of a few angstrom ngstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 angstrom and therefore have a strong influence on the efficiency of the conformational search during docking.
Citation Count: 0
Docking-based virtual screening for potential activity against bacterial pyruvate kinase
(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra
[Abstract Not Available]
Citation Count: 28
Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor
(Bmc, 2013) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru Demet
Background: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.
Citation Count: 0
Effect of Intracellular Loop 3 on Intrinsic Dynamics of Human β2-Adrenergic Receptor
(Cell Press, 2014) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru Demet
[No Abstract Available]
Citation Count: 24
How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics
(Cell Press, 2015) Akdoğan, Ebru Demet; Fındık, Doğa; Akdoğan, Ebru Demet; Doruker, Pemra
The tunnel region at triosephosphate isomerase (TIM)'s dimer interface distant from its catalytic site is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor named bt10. Within the time frame of our MD simulations we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10 which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54000 MD snapshots. Using this computationally efficient technique we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly we observed allosteric changes in the catalytic loop's dynamics flexibility and correlations as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.
Citation Count: 0
Investigation of allosteric communication pathways in human beta 2-adrenergic receptor
(Wiley-Blackwell, 2015) Akdaş, Başak; Kürkçüoğlu, Özge; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation Count: 16
Investigation of Allosteric Coupling in Human Beta(2)-Adrenergic Receptor in the Presence of Intracellular Loop 3
(BMC, 2016) Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet
Background: This study investigates the allosteric coupling that exists between the intra- and extracellular parts of human beta(2)-adrenergic receptor (beta(2)-AR) in the presence of the intracellular loop 3 (ICL3) which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 mu s long MD run has revealed a transition to the so-called very inactive state of the receptor in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study we performed independent runs with a total duration of 4 mu s to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site). Results: In all three independent unrestrained runs (each 500 ns long) ICL3 preserved its initially packed/closed conformation within the studied time frame suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure whereas a relatively constrained/closed binding site hindered ICL3 packing. However the reverse operation i.e. opening of the packed ICL3 could not be realized by restraining the binding site region to a closed state. Thus any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds. Conclusions: Overall our simulations indicated that starting with very inactive states the receptor stayed almost irreversibly inhibited which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site induced the expected conformational changes in TM5 TM6 and consequently ICL3. Still once ICL3 was packed the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.
Citation Count: 0
Investigation of intrinsic dynamics and allosteric coupling in human beta 2-adrenergic receptor
(Springer, 2017) Özcan, Özer; Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation Count: 8
Ligand-binding affinity of alternative conformers of human beta(2)-adrenergic receptor in the presence of intracellular loop 3 (ICL3) and their potential use in virtual screening studies
(Wiley, 2019) Dilcan, Gonca; Doruker, Pemra; Akten, Ebru Demet
This study investigates the structural distinctiveness of orthosteric ligand-binding sites of several human beta(2) adrenergic receptor (beta(2)-AR) conformations that have been obtained from a set of independent molecular dynamics (MD) simulations in the presence of intracellular loop 3 (ICL3). A docking protocol was established in order to classify each receptor conformation via its binding affinity to selected ligands with known efficacy. This work's main goal was to reveal many subtle features of the ligand-binding site presenting alternative conformations which might be considered as either active- or inactive-like but mostly specific for that ligand. Agonists inverse agonists and antagonists were docked to each MD conformer with distinct binding pockets using different docking tools and scoring functions. Mostly favored receptor conformation persistently observed in all docking/scoring evaluations was classified as active or inactive based on the type of ligand's biological effect. Classified MD conformers were further tested for their ability to discriminate agonists from inverse agonists/antagonists and several conformers were proposed as important targets to be used in virtual screening experiments that were often limited to a single X-ray structure.