Browsing by Author "Cakan, Sibel"

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Citation Count: 1
Exploring Distinct Binding Site Regions of Beta(2)-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Scientific Technical Research Council Turkey-Tubitak, 2013) Cakan, Sibel; Akdoğan, Ebru Demet
beta(2)-Adrenergic receptor (beta(2)AR) is a G protein-coupled receptor that is highly flexible and able to recognize a wide range of ligands through its conformational variations. Active and inactive conformations revealed by recent crystallographic experiments do not provide a complete dynamic picture of the receptor especially in the binding site. In this study molecular dynamics (MD) simulation through a residue-based coarse-grained model is used as an alternative and efficient method to explore a wider conformational search space. The system was composed of beta(2)AR embedded into a 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane bilayer with surrounding water. A total of 6 mu s of simulation at constant NPT was performed for a system of 6868 coarse-grained beads. The system reached equilibrium at around 0.1 mu s. The overall 3-dimensional structure was well preserved throughout the simulation. Local residue-based fluctuations were in good agreement with fully atomistic MD simulations. Four distinct snapshots were selected and reverse-mapped to all-atom representations with around 65000 atoms. Each reverse-mapped system was later subjected to 100 ns of MD simulation for equilibration. Root mean square deviation clustering analysis yielded distinct receptor conformers for the binding site regions which were suggested to be alternative representations of the binding pocket and thus were proposed as plausible targets in docking-based virtual screening experiments for the discovery of novel antagonists.
Poz- Adrenerjik Reseptörün Kaba Taneli Moleküler Dinamik Simülasyonu ile Farklı Konformasyonlarının Araştırılması
(Kadir Has Üniversitesi, 2012) Cakan, Sibel; Akten, Ebru Demet
ß2 adrenergic receptor (ß2AR) is a G protein-coupled receptor, which belongs to thelargest family of membrane proteins and is the target of many drugs. ß2AR is highlyflexible and, able to recognize a wide range of ligands through its conformationalvariations. Although recent crystallographic experiments have revealed active andinactive conformations, they are not sufficient for deciphering the whole receptor?sdynamics. Molecular dynamics (MD) simulation is an alternative and efficientmethod to understand the protein dynamics. However, traditional all-atomsimulations do not reach the millisecond time scales at which many biologicalprocesses occur. Thus, coarse-grained (CG) modeling is used to reduce the numberof degrees of freedom. The system was composed of ß2AR embedded into apalmitoyl-oleoyl-phosphatidylcholine (POPC) membrane bilayer with surroundingwater. Main purpose of using a CG model is to explore a wider conformational spacethat would not be reachable via all-atom models. The local fluctuations were in goodagreement with all-atom simulations. Four snapshots were selected and reversemappedto all-atom representations. Each was later subjected to 100 ns MDsimulation for equilibration. RMSD clustering yielded distinct receptor conformersthat are both energetically and structurally acceptable. PCA analysis of CG-MDsimulations showed that the first five principle modes explained only 50% of theoverall dynamics compared to 85% in all-atom simulations. Maximum overlap valuebetween eigenvectors of CG and all-atom was determined as 0.46. Normalizedorientational cross-correlations between residue fluctuations revealed weakercorrelations in CG simulations compared to all-atomAPPEND