Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Tekpinar, Mustafa; Yildirim, Ahmet; Wassenaar, Tsjerk A.

doi:10.1007/s00249-015-1067-0

Cited by 6 publications

(6 citation statements)

References 42 publications

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“…Figure shows the first eigenvector for each system, determined and drawn using a previously developed PCA module for PyMOL. , These results show that in the individual systems the first eigenvector captures between 10 and 30% of the total motility, suggesting that there is little concerted motion. However, it can also be seen that the contribution of the first eigenvector is more important in the systems with more dynamics, notably the Ca 2+ -bound form, where the first eigenvector captures between 20 and 30% of the total variance in the system.…”

Section: Resultsmentioning

confidence: 96%

“…Performing PCA on a joint set of trajectories provides a mixed view of the variance structure between trajectories and within trajectories and allows assessment of the relative importance of the two sources by plotting the projections and marking the average structures. , The joint covariance matrix was determined after fitting all structures to a common reference. We also included all structures obtained by swapping the two chains in the dimers, as both chains are thermodynamically indistinguishable and any asymmetry should be considered equally likely for the other permutation.…”

Section: Resultsmentioning

confidence: 99%

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Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

2021

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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 Ca 2+ and nonmuscle myosin IIA (NMIIA), we used molecular dynamics simulations to investigate apo S100A4 and four holo S100A4 structures: S100A4 bound to Ca 2+ , S100A4 bound to NMIIA, S100A4 bound to Ca 2+ and NMIIA, and a mutated S100A4 bound to Ca 2+ and NMIIA. Our results show that two competing factors, namely, Ca 2+ -induced activation and NMIIA-induced inhibition, modulate the dynamics of S100A4 in a competitive manner. Moreover, Ca 2+ 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 Ca 2+ the S100A4−NMIIA interaction is weak compared to that of between S100A4 bound to Ca 2+ 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 Ca 2+ , 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 Ca 2+ and NMIIA.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

2021

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“…These proteins do not have anything in common except FliM–FliG complex, which is a heterodimer of FliG and FliM proteins. Even though the main purpose of this study is to investigate the degree of agreement of linear correlations obtained with all-atom MD and ENM-based NMA, we should note that Hp-MTAN and CAP are well-known to have allosteric interactions. , …”

Section: Methodsmentioning

confidence: 99%

“…Even though the main purpose of this study is to investigate the degree of agreement of linear correlations obtained with all-atom MD and ENM-based NMA, we should note that Hp-MTAN and CAP are well-known to have allosteric interactions. 26,27 Methods. Molecular Dynamics Simulations.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Only a Subset of Normal Modes is Sufficient to Identify Linear Correlations in Proteins

Tekpinar¹,

Yildirim

2018

J. Chem. Inf. Model.

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Identification 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.

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“…Harmer et al, using Proflex, measured the global hydrogen bond network of GmhA and discovered that the catalytic pocket zinc of the second dimer showed greater stability and higher Lewis acidity, causing improved substrate affinity when the second substrate attached to the second dimer of GmhA rather than binding to another subunit . An example of this is 5′-methylthioadenosine nucleosidase, where the reaction can only proceed once D198 has been protonated. , …”

Section: Cooperativity and Dynamics Of Homodimeric Enzymes In Catalysismentioning

confidence: 99%

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes

Chen

Sun

2023

Chem. Rev.

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A survey of protein databases indicates that the majority of enzymes exist in oligomeric forms, with about half of those found in the UniProt database being homodimeric. Understanding why many enzymes are in their dimeric form is imperative. Recent developments in experimental and computational techniques have allowed for a deeper comprehension of the cooperative interactions between the subunits of dimeric enzymes. This review aims to succinctly summarize these recent advancements by providing an overview of experimental and theoretical methods, as well as an understanding of cooperativity in substrate binding and the molecular mechanisms of cooperative catalysis within homodimeric enzymes. Focus is set upon the beneficial effects of dimerization and cooperative catalysis. These advancements not only provide essential case studies and theoretical support for comprehending dimeric enzyme catalysis but also serve as a foundation for designing highly efficient catalysts, such as dimeric organic catalysts. Moreover, these developments have significant implications for drug design, as exemplified by Paxlovid, which was designed for the homodimeric main protease of SARS-CoV-2.

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Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Cited by 6 publications

References 42 publications

Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

Only a Subset of Normal Modes is Sufficient to Identify Linear Correlations in Proteins

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes

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Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Cited by 6 publications

References 42 publications

Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

Competing Roles of Ca2+ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

Only a Subset of Normal Modes is Sufficient to Identify Linear Correlations in Proteins

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes

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Product

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Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4

Competing Roles of Ca²⁺ and Nonmuscle Myosin IIA on the Dynamics of the Metastasis-Associated Protein S100A4