scholarly journals l-Malate (−2) Protonation State is Required for Efficient Decarboxylation to l-Lactate by the Malolactic Enzyme of Oenococcus oeni

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3431
Author(s):  
Waldo Acevedo ◽  
Pablo Cañón ◽  
Felipe Gómez-Alvear ◽  
Jaime Huerta ◽  
Daniel Aguayo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Malic Acid ◽  
Sequence Similarity ◽  
Isothermal Calorimetry ◽  
Homology Model ◽  
Binding Pocket ◽  
Oenococcus Oeni ◽  
Ligand Docking ◽  
Malolactic Enzyme ◽  
Dynamics Simulations

Malolactic fermentation (MLF) is responsible for the decarboxylation of l-malic into lactic acid in most red wines and some white wines. It reduces the acidity of wine, improves flavor complexity and microbiological stability. Despite its industrial interest, the MLF mechanism is not fully understood. The objective of this study was to provide new insights into the role of pH on the binding of malic acid to the malolactic enzyme (MLE) of Oenococcus oeni. To this end, sequence similarity networks and phylogenetic analysis were used to generate an MLE homology model, which was further refined by molecular dynamics simulations. The resulting model, together with quantum polarized ligand docking (QPLD), was used to describe the MLE binding pocket and pose of l-malic acid (MAL) and its l-malate (−1) and (−2) protonation states (MAL− and MAL2−, respectively). MAL2− has the lowest ∆Gbinding, followed by MAL− and MAL, with values of −23.8, −19.6, and −14.6 kJ/mol, respectively, consistent with those obtained by isothermal calorimetry thermodynamic (ITC) assays. Furthermore, molecular dynamics and MM/GBSA results suggest that only MAL2− displays an extended open conformation at the binding pocket, satisfying the geometrical requirements for Mn2+ coordination, a critical component of MLE activity. These results are consistent with the intracellular pH conditions of O. oeni cells—ranging from pH 5.8 to 6.1—where the enzymatic decarboxylation of malate occurs.

scholarly journals Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
K. K. Abelak ◽  
D. Bishop-Bailey ◽  
I. Nobeli
Keyword(s):  
Molecular Dynamics ◽  
Arachidonic Acid ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Homology Model ◽  
Cytochrome P450 Enzyme ◽  
Wild Type ◽  
Substrate Preferences ◽  
P450 Enzyme ◽  
Dynamics Simulations

Abstract Objectives The data presented here is part of a study that was aimed at characterizing the molecular mechanisms of polyunsaturated fatty acid metabolism by CYP2J2, the main cytochrome P450 enzyme active in the human cardiovasculature. This part comprises the molecular dynamics simulations of the binding of three eicosanoid substrates to wild type and mutant forms of the enzyme. These simulations were carried out with the aim of dissecting the importance of individual residues in the active site and the roles they might play in dictating the binding and catalytic specificity exhibited by CYP2J2. Data description The data comprise: (a) a new homology model of CYP2J2, (b) a number of predicted low-energy complexes of CYP2J2 with arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, produced with molecular docking and (c) a series of molecular dynamics simulations of the wild type and four mutants interacting with arachidonic acid as well as simulations of the wild type interacting with the two other eicosanoid ligands. The simulations may be helpful in identifying the determinants of substrate specificity of this enzyme and in unraveling the role of individual mutations on its function. They may also help guide the generation of mutants with altered substrate preferences.

Computational Design of Thiourea-based Cyclophane Sensors for Small Anions

2012 ◽  
Vol 65 (3) ◽  
pp. 303 ◽  
Author(s):  
Huifang Xie ◽  
Ming Wah Wong
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Density Functional ◽  
Computational Design ◽  
Binding Pocket ◽  
Solvent Medium ◽  
Guest Binding ◽  
Molecular Dynamics Calculations ◽  
Anion Complexes ◽  
Dynamics Simulations

The host–guest binding properties of a tri-thiourea cyclophane receptor (1) with several common anions have been investigated using density functional theory (DFT) and molecular dynamics calculations. Receptor 1 is predicted to be an effective receptor for binding small halogen and Y-shaped (NO3– and AcO–) anions in the gas phase, cyclohexane and chloroform. The calculated order of anion binding affinity for the receptor 1 in chloroform is F– > Cl– > AcO– > NO3– >Br– > H2PO4– > HSO4–. The binding free energies are strongly influenced by a dielectric solvent medium. The structures of the receptor–anion complexes are characterized by multiple (typically 6) hydrogen bonds in all cases. The overall binding affinity of various anions is determined by the basicity of anion, size and shape of the binding site, and solvent medium. Explicit chloroform solvent molecular dynamics simulations of selected receptor–anion complexes reveal that the anions are strongly bound within the binding pocket via hydrogen-bonding interactions to all the receptor protons throughout the simulation. A sulfur analogue of receptor 1 (2), with a larger central cavity, is shown to be a more effective sensor than 1 for small anions. Two different approaches to develop the thiourea-based cyclophane receptor into a chromogenic sensor were examined.

Structural insights into the binding mode of d-sorbitol with sorbitol dehydrogenase using QM-polarized ligand docking and molecular dynamics simulations

2016 ◽  
Vol 114 ◽  
pp. 244-256 ◽  
Author(s):  
Chandrabose Selvaraj ◽  
Gopinath Krishnasamy ◽  
Sujit Sadashiv Jagtap ◽  
Sanjay K.S. Patel ◽  
Saurabh Sudha Dhiman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Mode ◽  
Sorbitol Dehydrogenase ◽  
Ligand Docking ◽  
Dynamics Simulations ◽  
Structural Insights

scholarly journals Extracellular Cation Binding Pocket Is Essential For Ion Conduction Of OsHKT2;2

2018 ◽  
Author(s):  
Janin Riedelsberger ◽  
Ariela Vergara-Jaque ◽  
Miguel Piñeros ◽  
Ingo Dreyer ◽  
Wendy González
Keyword(s):  
Protein Interactions ◽  
Mutual Effect ◽  
Homology Model ◽  
Binding Pocket ◽  
Cation Binding ◽  
Ion Binding ◽  
Salt Bridges ◽  
Extracellular Medium ◽  
Dynamics Simulations ◽  
Sodium And Potassium

AbstractHKT channels mediate sodium uniport or sodium and potassium symport in plants. Monocotyledons express a higher number of HKT proteins than dicotyledons, and it is only within this clade of HKT channels that cation symport mechanisms are found. The prevailing ion composition in the extracellular medium affects the transport abilities of various HKT channels by changing their selectivity or ion transport rates. How this mutual effect is achieved at the molecular level is still unknown. Here, we built a homology model of the monocotyledonous OsHKT2;2, which shows sodium and potassium symport activity, and performed molecular dynamics simulations in the presence of sodium and potassium ions. By analyzing ion-protein interactions, we identified a cation binding pocket on the extracellular protein surface, which is formed by residues P71, D75, D501 and K504. Proline and the two aspartate residues coordinate cations, while K504 forms salt bridges with D75 and D501 and may be involved in the forwarding of cations towards the pore entrance. Functional validation via electrophysiological experiments confirmed the biological relevance of the predicted ion binding pocket and identified K504 as a central key residue. Mutation of the cation coordinating residues affected the functionality of HKT only slightly. Additional in silico mutants and simulations of K504 supported experimental results.

scholarly journals Molecular Dynamics Simulations for Biological Systems

2017 ◽  
pp. 1044-1071 ◽  
Author(s):  
Prerna Priya ◽  
Minu Kesheri ◽  
Rajeshwar P. Sinha ◽  
Swarna Kanchan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Biological Molecules ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Protein Protein Interaction ◽  
Dynamics Simulations

Molecular dynamics simulation is an important tool to capture the dynamicity of biological molecule and the atomistic insights. These insights are helpful to explore biological functions. Molecular dynamics simulation from femto seconds to milli seconds scale give a large ensemble of conformations that can reveal many biological mysteries. The main focus of the chapter is to throw light on theories, requirement of molecular dynamics for biological studies and application of molecular dynamics simulations. Molecular dynamics simulations are widely used to study protein-protein interaction, protein-ligand docking, effects of mutation on interactions, protein folding and flexibility of the biological molecules. This chapter also deals with various methods/algorithms of protein tertiary structure prediction, their strengths and weaknesses.

scholarly journals Exchange of water for sterol underlies sterol egress from a StARkin domain

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
George Khelashvili ◽  
Neha Chauhan ◽  
Kalpana Pandey ◽  
David Eliezer ◽  
Anant K Menon
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Binding Pocket ◽  
Yeast Cells ◽  
Endoplasmic Reticulum Membrane ◽  
Polar Residues ◽  
Dynamics Simulations

Previously we identified Lam/GramD1 proteins, a family of endoplasmic reticulum membrane proteins with sterol-binding StARkin domains that are implicated in intracellular sterol homeostasis. Here, we show how these proteins exchange sterol molecules with membranes. An aperture at one end of the StARkin domain enables sterol to enter/exit the binding pocket. Strikingly, the wall of the pocket is longitudinally fractured, exposing bound sterol to solvent. Large-scale atomistic molecular dynamics simulations reveal that sterol egress involves widening of the fracture, penetration of water into the cavity, and consequent destabilization of the bound sterol. The simulations identify polar residues along the fracture that are important for sterol release. Their replacement with alanine affects the ability of the StARkin domain to bind sterol, catalyze inter-vesicular sterol exchange and alleviate the nystatin-sensitivity of lam2Δ yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.

Molecular Dynamics Simulations for Biological Systems

2016 ◽  
pp. 286-313 ◽  
Author(s):  
Prerna Priya ◽  
Minu Kesheri ◽  
Rajeshwar P. Sinha ◽  
Swarna Kanchan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Biological Molecules ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Protein Protein Interaction ◽  
Dynamics Simulations

Molecular dynamics simulation is an important tool to capture the dynamicity of biological molecule and the atomistic insights. These insights are helpful to explore biological functions. Molecular dynamics simulation from femto seconds to milli seconds scale give a large ensemble of conformations that can reveal many biological mysteries. The main focus of the chapter is to throw light on theories, requirement of molecular dynamics for biological studies and application of molecular dynamics simulations. Molecular dynamics simulations are widely used to study protein-protein interaction, protein-ligand docking, effects of mutation on interactions, protein folding and flexibility of the biological molecules. This chapter also deals with various methods/algorithms of protein tertiary structure prediction, their strengths and weaknesses.

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