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Öğe Ab initio calculation of the structural, elastic, electronic, and linear optical properties of ZrPtSi and TiPtSi ternary compounds(2012) Koc, Husnu; Yildirim, Ahmet; Tetik, Erkan; Deligoz, EnginThe structural, elastic, electronic, and optical properties of orthorhombic ZrPtSi and TiPtSi ternary compounds are investigated using the norm-conserving pseudopotentials within the generalized gradient approximation (GGA) in the frame of density functional theory. The calculated lattice param- eters have been in agreement with the available experimental data. The second-order elastic constants have been calculated, and the other related quantities such as the Young’s modulus, shear modulus, Poisson’s ratio, anisotropy factor, sound velocities, and Debye temperature have also been estimated. The electronic structure of ZrPtSi and TiPtSi compounds are calculated by using the first principles GW and GGA approximations. The real and imaginary parts of the dielectric function and the optical constants such as the optical dielectric constant and the effective number of electrons per unit cell are also presented.Öğe Ab initio calculations of the elastic, electronic, optical, and vibrational properties of PdGa compound under pressure(2012) Koc, Husnu; Yildirim, Ahmet; Deligoz, EnginThe structural, elastic, electronic, optical, and vibrational properties of cubic PdGa compound are investigated using the norm-conserving pseudopotentials within the local density approximation (LDA) in the framework of the density functional theory. The calculated lattice constant has been compared with the experimental value and has been found to be in good agreement with experimental data. The obtained electronic band structures show that PdGa compound has no band gap. The second-order elastic constants have been calculated, and the other related quantities such as the Young's modulus, shear modulus, Poisson's ratio, anisotropy factor, sound velocities, and Debye temperature have also been estimated. Our calculated results of elastic constants show that this compound is mechanically stable. Furthermore, the real and imaginary parts of the dielectric function and the optical constants such as the electron energy-loss function, the optical dielectric constant and the effective number of electrons per unit cell are calculated and presented in the study. The phonon dispersion curves are also derived using the direct method.Öğe Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches(Nature Research, 2021) Gapsys, Vytautas; Yildirim, Ahmet; Aldeghi, Matteo; Khalak, Yuriy; van der Spoel, David; de Groot, Bert L.Molecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein-ligand binding affinity.Öğe Binding of Pollutants to Biomolecules: A Simulation Study(2016) Yildirim, Ahmet; Zhang, Jin; Manzetti, Sergio; van der Spoel, DavidA number of cases around the world have been reported where animals were found dead or dying with symptoms resembling a thiamine (vitamin B) deficiency, and for some of these, a link to pollutants has been suggested. Here, we investigate whether biomolecules involved in thiamin binding and transport could be blocked by a range of different pollutants. We used in silico docking of five compound classes (25 compounds in total) to each of five targets (prion protein, ECF-type ABC transporter, thi-box riboswitch receptor, thiamin pyrophosphokinase, and YKoF protein) and subsequently performed molecular dynamics (MD) simulations to assess the stability of the complexes. The compound classes were thiamin analogues (control), pesticides, veterinary medicines, polychlorinated biphenyls, and dioxins, all of which are prevalent in the environment to some extent. A few anthropogenic compounds were found to bind the ECF-type ABC transporter, but none binds stably to prion protein. For the riboswitch, most compounds remained in their binding pockets during 50 ns of MD simulation, indicating that RNA provides a promiscuous binding site. In both YKoF and thiamin pyrophosphokinase (TPK), most compounds remain tightly bound. However, TPK biomolecules undergo pollutant-induced conformational changes. Although most compounds are found to bind to some of these targets, a larger data set is needed along with more quantitative methods like free energy perturbation calculations before firm conclusions can be drawn. This study is in part a test bed for large-scale quantitative computational screening of interactions between biological entities and pollutant molecules.Öğe Building Quantitative Bridges between Dynamics and Sequences of SARS-CoV-2 Main Protease and a Diverse Set of Thirty-Two Proteins(Amer Chemical Soc, 2023) Yildirim, Ahmet; Tekpinar, MustafaProteases are major drug targets for many viral diseases. However, mutations can render several antiprotease drugs inefficient rapidly even though these mutations may not alter protein structures significantly. Understanding relations between quickly mutating residues, protease structures, and the dynamics of the proteases is crucial for designing potent drugs. Due to this reason, we studied relations between the evolutionary information on residues in the amino acid sequences and protein dynamics for SARS-CoV-2 main protease. More precisely, we analyzed three dynamical quantities (Schlitter entropy, root-mean-square fluctuations, and dynamical flexibility index) and their relation to the amino acid conservation extracted from multiple sequence alignments of the main protease. We showed that a quantifiable similarity can be built between a sequence-based quantity called Jensen-Shannon conservation and those three dynamical quantities. We validated this similarity for a diverse set of 32 different proteins, other than the SARS-CoV-2 main protease. We believe that establishing these kinds of quantitative bridges will have larger implications for all viral proteases as well as all proteins.Öğe Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4(Amer Chemical Soc, 2021) Yildirim, Ahmet; Tekpinar, Mustafa; Wassenaar, Tsjerk A.The calcium-binding protein S100A4 plays an important role in a wide range of biological processes such as cell motility, invasion, angiogenesis, survival, differentiation, contractility, and tumor metastasis and interacts with a range of partners. To understand the functional roles and interplay of S100A4 binding partners such as Ca2+ and nonmuscle myosin IIA (NMIIA), we used molecular dynamics simulations to investigate apo S100A4 and four holo S100A4 structures: S100A4 bound to Ca2+, S100A4 bound to NMIIA, S100A4 bound to Ca2+ and NMIIA, and a mutated S100A4 bound to Ca2+ and NMIIA. Our results show that two competing factors, namely, Ca2+-induced activation and NMIIA-induced inhibition, modulate the dynamics of S100A4 in a competitive manner. Moreover, Ca2+ binding results in enhanced dynamics, regulating the interactions of S100A4 with NMIIA, while NMIIA induces asymmetric dynamics between the chains of S100A4. The results also show that in the absence of Ca2+ the S100A4-NMIIA interaction is weak compared to that of between S100A4 bound to Ca2+ and NMIIA, which may offer a quick response to dropping calcium levels. In addition, certain mutations are shown to play a marked role on the dynamics of S100A4. The results described here contribute to understanding the interactions of S100A4 with NMIIA and the functional roles of Ca2+, NMIIA, and certain mutations on the dynamics of S100A4. The results of this study could be interesting for the development of inhibitors that exploit the shift of balance between the competing roles of Ca2+ and NMIIA.Öğe First-principles study of the structural, elastic, electronic, optical, and vibrational properties of intermetallic Pd2Ga(2012) Yildirim, Ahmet; Koc, Husnu; Deligoz, EnginThe structural, elastic, electronic, optical, and vibrational properties of the orthorhombic Pd 2 Ga compound are investigated using the norm-conserving pseudopotentials within the local density approximation in the frame of density functional theory. The calculated lattice parameters have been compared with the experimental values and found to be in good agreement with these results. The second-order elastic constants and the other relevant quantities, such as the Young’s modulus, shear modulus, Poisson’s ratio, anisotropy factor, sound velocity, and Debye temperature, have been calculated. It is shown that this compound is mechanically stable after analysing the calculated elastic constants. Furthermore, the real and imaginary parts of the dielectric function and the optical constants, such as the optical dielectric constant and the effective number of electrons per unit cell, are calculated and presented. The phonon dispersion curves are derived using the direct method. The present results demonstrate that this compound is dynamically stable.Öğe Impact of dimerization and N3 binding on molecular dynamics of SARS-CoV and SARS-CoV-2 main proteases(Taylor & Francis Inc, 2022) Tekpinar, Mustafa; Yildirim, AhmetSARS-CoV-2 main protease is one of the major targets in drug development efforts against Covid-19. Even though several structures were reported to date, its dynamics is not understood well. In particular, impact of dimerization and ligand binding on the dynamics is an important issue to investigate. In this study, we performed molecular dynamics simulations of SARS-CoV and SARS-CoV-2 main proteases to investigate influence of dimerization on the dynamics by modeling monomeric and dimeric apo and holo forms. The dimerization causes an organization of the interdomain dynamics as well as some local structural changes. Moreover, we investigated impact of a peptide mimetic (N3) on the dynamics of SARS-CoV and SARS-CoV-2 Mpro. The ligand binding to the dimeric forms causes some key local changes at the dimer interface and it causes an allosteric interaction between the active sites of two protomers. Our results support the idea that only one protomer is active on SARS-CoV-2 due to this allosteric interaction. Additionally, we analyzed the molecular dynamics trajectories from graph theoretical perspective and found that the most influential residues - as measured by eigenvector centrality - are a group of residues in active site and dimeric interface of the protease. This study may form a bridge between what we know about the dynamics of SARS-CoV and SARS-CoV-2 Mpro. We think that enlightening allosteric communication of the active sites and the role of dimerization in SARS-CoV-2 Mpro can contribute to development of novel drugs against this global health problem as well as other similar proteases. Communicated by Ramaswamy H. SarmaÖğe Investigation of anisotropic thermal conductivity of uniaxial and biaxial Gay-Berne particles with molecular dynamics simulation(Taylor & Francis Ltd, 2011) Yildirim, Ahmet; Eroglu, Erol; Yilmaz, SuleymanIn this study, we investigated uniaxial and biaxial Gay-Berne (GB) particles with the help of the molecular dynamics (MD) simulation. Anisotropic thermal conductivities of the uniaxial and biaxial GB liquid crystal molecules were calculated both in the random molecular orientation and in the molecular orientations of 0 degrees, 45 degrees and 90 degrees using the Muller-Plathe method. In the uniaxial molecules, it was found that the thermal conductivity ratios between the parallel and perpendicular components for the smectic and nematic phases are about 2.2:1 and 2.8:1, respectively. As for biaxial molecules, these ratios between the parallel and perpendicular components of molecules for the smectic and nematic phases are about 3.9:1 and 3.8:1, respectively.Öğe Investigation of anisotropic thermal conductivity of uniaxial and biaxial Gay–Berne particles with molecular dynamics simulation(2011) Yildirim, Ahmet; Eroglu, Erol; Yilmaz, SuleymanIn this study, we investigated uniaxial and biaxial Gay– Berne (GB) particles with the help of the molecular dynamics (MD) simulation. Anisotropic thermal conductivities of the uniaxial and biaxial GB liquid crystal molecules were calculated both in the random molecular orientation and in the molecular orientations of 08, 458 and 908 using the Müller-Plathe method. In the uniaxial molecules, it was found that the thermal conductivity ratios between the parallel and perpendicular components for the smectic and nematic phases are about 2.2:1 and 2.8:1, respectively. As for biaxial molecules, these ratios between the parallel and perpendicular components of molecules for the smectic and nematic phases are about 3.9:1 and 3.8:1, respectively.Öğe Molecular dynamics investigation of Helicobacter pylori chemotactic protein CheY1 and two mutants(2014) Yildirim, Ahmet; Tekpinar, Mustafa; A. Wassenaar, TsjerkCheY is a chemotactic response regulator protein modulating the rotation direction of bacterial flagellar motors. It plays an important role in the colonization and infection of Helicobacter pylori (H. pylori), which is a common pathogen. Recently, the structure of CheY1 of H. pylori (HpCheY1) was solved, showing similarities and differences with CheY from E. coli. Here, we report 200 ns atomistic molecular dynamics (MD) simulations of HpCheY1 and two mutants. The results suggest that the surface of HpCheY1 has regions with increased affinity for Mg²⁺. In addition, wildtype HpCheY1 (WT HpCheY1) shows characteristic dynamics in helix 4, which is involved in FliM binding. This dynamics is altered in the D53A mutant and completely suppressed in the T84A mutant. The results are discussed in relation to the binding and function of HpCheY1.Öğe Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase(2015) Tekpinar, Mustafa; Yildirim, Ahmet; A. Wassenaar, TsjerkThe protein 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is involved in the quorum sensing of several bacterial species, including Helicobacter pylori. In particular, these bacteria depend on MTAN for synthesis of vitamin K2 homologs. The residue D198 in the active site of MTAN seems to be of crucial importance, by acting as a hydrogen-bond acceptor for the ligand. In this study, we investigated the conformation and dynamics of apo and holo H. pylori MTAN (HpMTAN), and assessed the effect of protonation of D198 by use of molecular dynamics simulations. Our results show that protonation of the active site of HpMTAN can cause a conformational transition from a closed state to an open state even in the absence of substrate, via inter-chain mechanical coupling.Öğe Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5?-methylthioadenosine/S-adenosylhomocysteine nucleosidase(Springer Verlag, 2015) Tekpinar, Mustafa; Yildirim, Ahmet; Wassenaar, Tsjerk A.The protein 5?-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is involved in the quorum sensing of several bacterial species, including Helicobacter pylori. In particular, these bacteria depend on MTAN for synthesis of vitamin K2 homologs. The residue D198 in the active site of MTAN seems to be of crucial importance, by acting as a hydrogen-bond acceptor for the ligand. In this study, we investigated the conformation and dynamics of apo and holo H. pylori MTAN (HpMTAN), and assessed the effect of protonation of D198 by use of molecular dynamics simulations. Our results show that protonation of the active site of HpMTAN can cause a conformational transition from a closed state to an open state even in the absence of substrate, via inter-chain mechanical coupling. © 2015, European Biophysical Societies' Association.Öğe Numerical Determination of Thermal-Diffusivity Coefficients of Some Nematic Liquid Crystals in Situ(2009) Yilmaz, Suleyman; Yildirim, AhmetIn this study, a new experimental study has been implemented to deter- mine the thermal-diffusivity parameters of industrial nematic liquid crystals, 4-pentyl- 4 -cyanobiphenyl (5CB) and 4 -octyl-4-cyanobiphenyl (8CB), both numerically by using the finite difference method (FDM) for forward solutions and experimentally by measuring the temperature variation with time and position. The most important parts of this experimental study are the heating system and the liquid crystal cell, which were constructed in-house to determine the temperatures of the materials in situ. Four different positions for local measurements have been studied, and the opti- mum graph of this variation has been determined. The experimental and theoretical results of this study are consistent with previous measurements performed by means of a conventional thermal technique.Öğe Only a Subset of Normal Modes is Sufficient to Identify Linear Correlations in Proteins(Amer Chemical Soc, 2018) Tekpinar, Mustafa; Yildirim, AhmetIdentification of correlated residues in proteins is very important for many areas of protein research such as drug design, protein domain classification, signal transmission, allostery and mutational studies. Pairwise residue correlations in proteins can be obtained from experimental and theoretical ensembles. Since it is difficult to obtain proteins in various conformational states experimentally, theoretical methods such as all-atom molecular dynamics simulations and normal-mode analysis are commonly used methods to obtain protein ensembles and, therefore, pairwise residue correlations. The extent of agreement for the correlations obtained with all-atom molecular dynamics and elastic network model based normal-mode analysis is an important issue to investigate due to orders of magnitude computational advantage in terms of wall time for normal-mode based calculation. We performed multiple microsecond long equilibrium classical molecular dynamics simulations for six proteins. We calculated normalized dynamical cross-correlations and linear mutual information as pairwise residue correlations from the trajectories of these simulations. Then, we calculated the same pairwise residue correlations with two elastic network model based normal-mode analysis methods and compared our results with the former. The results show that elastic network model based normal-mode analysis can provide a fast and accurate estimation of linear correlations within proteins. Finally, we observed that only a subset of modes is sufficient to obtain linear correlations in proteins. This conclusion has crucial implications for understanding correlations within very large protein assemblies such as viral capsids.Öğe Only a Subset of Normal Modes is Sufficient to Identify Linear Correlations in Proteins.(2018) Tekpinar, Mustafa; Yildirim, AhmetIdentification of correlated residues in proteins is very important for many areas of protein research such as drug design, protein domain classification, signal transmission, allostery and mutational studies. Pairwise residue correlations in proteins can be obtained from experimental and theoretical ensembles. Since it is difficult to obtain proteins in various conformational states experimentally, theoretical methods such as all-atom molecular dynamics simulations and normal-mode analysis are commonly used methods to obtain protein ensembles and, therefore, pairwise residue correlations. The extent of agreement for the correlations obtained with all-atom molecular dynamics and elastic network model based normal-mode analysis is an important issue to investigate due to orders of magnitude computational advantage in terms of wall time for normal-mode based calculation. We performed multiple microsecond long equilibrium classical molecular dynamics simulations for six proteins. We calculated normalized dynamical cross-correlations and linear mutual information as pairwise residue correlations from the trajectories of these simulations. Then, we calculated the same pairwise residue correlations with two elastic network model based normal-mode analysis methods and compared our results with the former. The results show that elastic network model based normal-mode analysis can provide a fast and accurate estimation of linear correlations within proteins. Finally, we observed that only a subset of modes is sufficient to obtain linear correlations in proteins. This conclusion has crucial implications for understanding correlations within very large protein assemblies such as viral capsids.Öğe Opening mechanism of adenylate kinase can vary according to selected molecular dynamics force field(2015) Unan, Hulya; Yildirim, Ahmet; Tekpinar, MustafaAdenylate kinase is a widely used test case for many conformational transition studies. It performs a large conformational transition between closed and open conformations while performing its catalytic function. To understand conformational transition mechanism and impact of force field choice on E. Coli adenylate kinase, we performed all-atom explicit solvent classical molecular dynamics simulations starting from the closed conformation with four commonly used force fields, namely, Amber99, Charmm27, Gromos53a6, Opls-aa. We carried out 40 simulations, each one 200 ns. We analyzed completely 12 of them that show full conformational transition from the closed state to the open one. Our study shows that different force fields can have a bias toward different transition pathways. Transition time scales, frequency of conformational transitions, order of domain motions and free energy landscapes of each force field may also vary. In general, Amber99 and Charmm27 behave similarly while Gromos53a6 results have a resemblance to the Opls-aa force field results.Öğe Optical Properties of Nematic Liquid Crystal (C 21 H 27 NO 2 S) Under AC/DC Electric Fields(2009) Emek, Mehriban; Besli, Nurettin; Yilmaz, Suleyman; Yildirim, AhmetIn this study, the effects of the phase transition on the optical transmittance of the nematic liquid crystal C21H27NO2S, 4′-isothiocyanatophenyl-4-pentylbicyclo[2,2,2]octane-1-carboxylate are investigated in terms of temperature variation and rotational angle of the polarizer through electro-optical methods under AC / DC electric fields. It is observed that the domain structure of the material is affected considerably by the applied electric field as the temperature changes. Under applied electric fields, the crystal-nematic (CN) phase-transition point changes and the behaviour of the liquid crystal in the phase-transition region shows some differences. The intensity of the light passing through the system under a DC electric field increases as the electric field rises. Nevertheless, the intensity of the transmitted light under an AC electric field increases at the beginning and then decreases as the electric field rises to a temperature of more than 355 K. These results can be explained through the formation of a domain structure during the phase-transition process and the light scattering caused by these structures.Öğe Propagation of uncertainty in physicochemical data to force field predictions(Amer Physical Soc, 2020) Yildirim, Ahmet; Ghahremanpour, Mohammad Mehdi; van der Spoel, DavidThe solvation free energy (SFE) is a key property in the thermodynamics of chemical processes. It can be evaluated using molecular simulations with good statistical accuracy. However, force field predictions exhibit systematic errors due to uncertainties in the parametrization. Here we evaluate how the uncertainty in physicochemical data underlying force fields propagates to SFE predictions. We find that the data contribution to the uncertainty in SFE is up to 25 times larger than the statistical uncertainty. The total uncertainty in the SFE in water is higher than in cyclohexane.Öğe Properties of Organic Liquids when Simulated with Long-Range Lennard-Jones Interactions(2015) M. Fischer, Nina; J. van Maaren, Paul; C. Ditz, Jonas; Yildirim, Ahmet; van der Spoel, DavidIn order to increase the accuracy of classical computer simulations, existing methodologies may need to be adapted. Hitherto, most force fields employ a truncated potential function to model van der Waals interactions, sometimes augmented with an analytical correction. Although such corrections are accurate for homogeneous systems with a long cutoff, they should not be used in inherently inhomogeneous systems such as biomolecular and interface systems. For such cases, a variant of the particle mesh Ewald algorithm (Lennard-Jones PME) was already proposed 20 years ago (Essmann et al. J. Chem. Phys. 1995, 103, 8577-8593), but it was implemented only recently (Wennberg et al. J. Chem. Theory Comput. 2013, 9, 3527-3537) in a major simulation code (GROMACS). The availability of this method allows surface tensions of liquids as well as bulk properties to be established, such as density and enthalpy of vaporization, without approximations due to truncation. Here, we report on simulations of ≈150 liquids (taken from a force field benchmark: Caleman et al. J. Chem. Theory Comput. 2012, 8, 61-74) using three different force fields and compare simulations with and without explicit long-range van der Waals interactions. We find that the density and enthalpy of vaporization increase for most liquids using the generalized Amber force field (GAFF, Wang et al. J. Comput. Chem. 2004, 25, 1157-1174) and the Charmm generalized force field (CGenFF, Vanommeslaeghe et al. J. Comput. Chem. 2010, 31, 671-690) but less so for OPLS/AA (Jorgensen and Tirado-Rives, Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6665-6670), which was parametrized with an analytical correction to the van der Waals potential. The surface tension increases by ≈10(-2) N/m for all force fields. These results suggest that van der Waals attractions in force fields are too strong, in particular for the GAFF and CGenFF. In addition to the simulation results, we introduce a new version of a web server, http://virtualchemistry.org, aimed at facilitating sharing and reuse of input files for molecular simulations.
