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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 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 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 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.
