Biyoinformatik ve Genetik Bölümü Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12469/46

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Classification of Distinct Conformers of Beta < 2-Adrenergic Receptor (beta 2-Ar) Based on Binding Affinity of Ligands Through Docking Studies
(Amer Chemical Soc, 2016) Akten, Ebru Demet; Dilcan, Gonca
B2AR reseptörü, akciğerlerin rahatlamasında ve kardiyovasküler fizyolojide rol oynamasıyla önemli bir ilaç hedefidir. Bu çalışmada, çeşitli B2AR konformasyonlarını aktif veya inaktif olarak sınıflandırmak amacıyla, aktivitesi bilinen ligantlar seçilerek onların bağlanma şekillerine göre bir sınıflandırma stratejisi oluşturulmuştur. Önceki bir çalışmada gerçekleştirilen, reseptörün inaktif halinin 2.8 μs'lik MD simülasyonunda, ligandın bağlanma bölgesinin farklı konformasyonları elde edilmiştir. Snapshotlar derlenerek bağlanma bölgesindeki beş anahtar rezidünün RMSD değerlerine göre gruplandırılmıştır. Toplamda 13 farklı konformasyon elde edilmiş ve 5 agonist, 4 ters agonist ve 4 antagonist molekülü her bir konformasyona ayrı ayrı ve 7 farklı skor fonksiyonu kullanılarak dock edilmiştir. En iyi yerleşen konformasyonlar bağlanma bölgesindeki anahtar rezidülerle olan yakınlığına göre seçilmiş ve hesaplanmıştır. Anahtar bölgeye yaklaşamayanlar elenmiş, kalanlar ise skor değerlerine göre sıralanmıştır. Bu sınıflandırma, kritik değerlendirme yapabilmek için MD konformasyonlarından önce aktivitesi bilinen aktif/inaktif kristal yapılara uygulanmıştır. Her skor fonksiyonu tarafından seçilen ve ilk 5'te bulunan MD konformasyonları aktif ve inaktif olarak sınıflandırılmıştır. Son olarak, MD konformasyonlarının ayırt ediciliğini analiz edebilmek için, seçilen bu konformasyonlar ile küçük bir dataset kullanılarak sanal tarama yapılmıştır. MD konformasyonlarının inaktif kristal yapıya göre antagonist/ters agonistler için daha seçici olduğu gözlemlenmiştir. Reseptörün alternatif konformasyonlarını üretmek ve onları sınıflandırmak, genellikle tek bir snaphot X-ray örneği ile sınırlandırılmış ilaç tasarımı çalışmalarında önemli rol oynamaktadır.
Comp 297-Experimental and Molecular Docking Simulation Studies of Histone Deacetylases (hdacs) Enzyme Inhibitors
(Amer Chemical Soc, 2007) Yelekçi, Kemal; Bora, Gamze; Dayangaç-Erden, Didem; Ayhan, Peruze; Dalkara, Sevim; Demir, Ayhan S.; Erdem-Yurter, Hayat
[Abstract Not Available]
Citation - WoS: 5
Citation - Scopus: 7
Computational Analysis of a Zn-Bound Tris(imidazolyl) Calix[6]arene Aqua Complex: Toward Incorporating Second-Coordination Sphere Effects Into Carbonic Anhydrase Biomimetics
(Amer Chemical Soc, 2013) Koziol, Lucas; Eşsiz, Şebnem; Wong, Sergio E.; Lau, Edmond Y.; Valdez, Carlos A.; Satcher, Joe H. Jr.; Aines, Roger D.; Lightstone, Felice C.
Molecular dynamics simulations and quantum-mechanical calculations were performed to characterize a supra-molecular tris(imidazolyl) calix[6]arene Zn2+ aqua complex as a biomimetic model for the catalyzed hydration of carbon dioxide to bicarbonate H2O + CO2 -> H+ + HCO3-. On the basis of potential-of-mean-force (PMF) calculations stable conformations had distorted 3-fold symmetry and supported either one or zero encapsulated water molecules. The conformation with an encapsulated water molecule is calculated to be lower in free energy than the conformation with an empty cavity (Delta G = 1.2 kcal/mol) and is the calculated free-energy minimum in solution. CO2 molecule partitioning into the cavity is shown to be very facile proceeding with a barrier of 1.6 kcal/mol from a weak encounter complex which stabilizes the species by about 1.0 kcal/mol. The stabilization energy of CO2 is calculated to be larger than that of H2O (Delta Delta G = 1.4 kcal/mol) suggesting that the complex will preferentially encapsulate CO2 in solution. In contrast the PMF for a bicarbonate anion entering the cavity is calculated to be repulsive in all nonbonding regions of the cavity due to the diameter of the calix[6]arene walls. Geometry optimization of the Zn-bound hydroxide complex with an encapsulated CO2 molecule showed that multiple noncovalent interactions direct the reactants into optimal position for nucleophilic addition to occur. The calixarene complex is a structural mimic of the hydrophilic/hydrophobic divide in the enzyme providing a functional effect for CO2 addition in the catalytic cycle. The results show that Zn-binding calix[6]arene scaffolds can be potential synthetic biomimetics for CO2 hydration catalysis both in terms of preferentially encapsulating CO2 from solution and by spatially fixing the reactive species inside the cavity.
In Silico Modeling of Dopamine Transporter and Design of Novel Neuroprotective Agents
(Amer Chemical Soc, 2016) Djikic, Teodora; Yelekci, Kemal
[Abstract Not Available]
Intermolecular Interactions in Human Hdac8 Crystal Structures and the Stability of Binding Modes of Co-Crystallized Inhibitors
(Amer Chemical Soc, 2019) Yelekçi, Kemal; Uba, Abdullahi Ibrahim
[Abstract Not Available]
Citation - WoS: 2
Citation - Scopus: 2
Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human Beta(2)-Adrenergic Receptor
(Amer Chemical Soc, 2019) Söğünmez, Nuray; Akten, Ebru Demet
The alternative inactive state of the human beta(2)-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3 which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover the extent motions decreased and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver follower relationship profiles. Prior to its packing freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed ICL3 controlled future fluctuations of nearby helices. Moreover two transmembrane helices (H5 and H6) started to control future fluctuations of a remote site the extracellular loop ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified in agreement with the receptor's well recognized feature which is the inverse proportionality between activity and the degree of coupling.
Medi 333-Histone Deacetylase Inhibition Activity of Resveratrol and Its Analogs
(Amer Chemical Soc, 2007) Dayangac-Erden, Didem; Ayhan, Peruze; Bora, Gamze; Yelekçi, Kemal; Dalkara, Sevim; Demir, Ayhan S.; Erdem-Yurter, Hayat
[Abstract Not Available]
Soman as a Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations
(Amer Chemical Soc, 2014) Bennion, Brian J.; Eşsiz, Şebnem; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.
[Abstract Not Available]
Thermal Rearrangement of 2-Acetoxy Trimethylbicyclo[3.1.0]hexane: Theoretical Elucidation of the Mechanism
(Amer Chemical Soc, 2007) Yelekçi, Kemal; Erdem, Safiye Sağ
[Abstract Not Available]

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