Assessing the capability of<i>in silico</i>mutation protocols for predicting the finite temperature conformation of amino acids

Ochoa, Rodrigo; Soler, Miguel A.; Laio, Alessandro; Cossio, Pilar

doi:10.1039/c8cp03826k

Cited by 19 publications

(21 citation statements)

References 57 publications

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“…The Nose-Hoover thermostat constant was utilized for fixing the temperature of the system at 310 K. To maintain the pressure of the system at fixed 1bar pressure, the Parrinello-Rahman pressure coupling method was used [28]. The electrostatic interactions were measured using the Particle Mesh Ewald (PME) method with 1.0 nm short-range electrostatic and van der Waals cutoffs [29,30]. Finally, for each complex, the MD simulation process was repeated twice for about 100 ns with time steps of 2 fs on equilibrated systems respectively.…”

Section: Molecular Docking and MD Simulation Analysismentioning

confidence: 99%

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

et al. 2020

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Calprotectin is a heterodimeric protein complex with two subunits called S100A8/A9. The protein has an essential role in inflammation process and various human diseases. It has the ability to bind to unsaturated fatty acids including Arachidonic acid, Oleic acid and etc., which could be considered as a major carrier for fatty acids. In this study we aimed to appraise the thermodynamics and structural changes of Calprotectin in presence of Arachidonic acid/Oleic acid) using docking and molecular dynami simulation method. To create the best conformation of Calprotectin-Oleic acid/Arachidonic acid complexes, the docking process was performed. The complexes with the best binding energy were selected as the models for molecular dynamics simulation process. Furthermore, the structural and thermodynamics properties of the complexes were evaluated too. The Root Mean Square Deviation and Root Mean Square Fluctuation results showed that the binding of Arachidonic acid/ Oleic acid to Calprotectin can cause the protein structural changes which was confirmed by Define Secondary Structure of Proteins results. Accordingly, the binding free energy results verified that binding of Oleic acid to Calprotectin leads to instability of S100A8/A9 subunits in the protein. Moreover, the electrostatic energy contribution of the complexes (Calprotectin-Oleic acid/Arachidonic acid) was remarkably higher than van der Waals energy. Thus, the outcome of this study confirm that Oleic acid has a stronger interaction with Calprotectin in comparison with Arachidonic acid. Our findings indicated that binding of unsaturated fatty acids to Calprotectin leads to structural changes of the S100A8/A9 subunits which could be beneficial to play a biological role in inflammation process.

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Section: Molecular Docking and MD Simulation Analysismentioning

confidence: 99%

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

et al. 2020

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“…The strategies are the sequence motif matrix, the machine learning tool NetMHCIIpan, the MD/scoring and backrub/scoring approaches, and the MM-PBSA calculations (see Methods). The peptide were selected based on criteria that facilitate the initial modelling of the rotamers (Ochoa et al, 2018), and the inclusion, in some cases, of additional flanking amino acids. Moreover, these peptides have available experimental binding data.…”

Section: Discussionmentioning

confidence: 99%

“…We modelled the selected peptides by iterative single substitutions of the peptide template sequence. The mutations were performed with the package fixbb from Rosetta (Loffler et al, 2017), which was compared in a previous study to other available mutation protocols (Ochoa et al, 2018). The method selects the most probable rotamer from a dictionary of backbonedependent conformations.…”

Section: Modelling and Simulations Of A Large Dataset Of Peptides Boumentioning

confidence: 99%

Impact of Structural Observables From Simulations to Predict the Effect of Single-Point Mutations in MHC Class II Peptide Binders

Ochoa

Laskowski

Thornton

et al. 2021

Front. Mol. Biosci.

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The prediction of peptide binders to Major Histocompatibility Complex (MHC) class II receptors is of great interest to study autoimmune diseases and for vaccine development. Most approaches predict the affinities using sequence-based models trained on experimental data and multiple alignments from known peptide substrates. However, detecting activity differences caused by single-point mutations is a challenging task. In this work, we used interactions calculated from simulations to build scoring matrices for quickly estimating binding differences by single-point mutations. We modelled a set of 837 peptides bound to an MHC class II allele, and optimized the sampling of the conformations using the Rosetta backrub method by comparing the results to molecular dynamics simulations. From the dynamic trajectories of each complex, we averaged and compared structural observables for each amino acid at each position of the 9°mer peptide core region. With this information, we generated the scoring-matrices to predict the sign of the binding differences. We then compared the performance of the best scoring-matrix to different computational methodologies that range in computational costs. Overall, the prediction of the activity differences caused by single mutated peptides was lower than 60% for all the methods. However, the developed scoring-matrix in combination with existing methods reports an increase in the performance, up to 86% with a scoring method that uses molecular dynamics.

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“…The Nose–Hoover thermostat constant was used for fixing the temperature of the system at 310 K. To maintain the pressure of the system at fixed 1 bar pressure, the Parrinello–Rahman pressure coupling method was used [20]. The electrostatic interactions were calculated using the Particle Mesh Ewald (PME) method with 1.0 nm short-range electrostatic and van der Waals cutoffs [21, 22]. To evaluate the effects of calcium ion on dimerization process, the A9 with and without calcium was used.…”

Section: Methodsmentioning

confidence: 99%

In silico assessment of human Calprotectin subunits (S100A8/A9) in presence of sodium and calcium ions using Molecular Dynamics simulation approach

et al. 2019

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Calprotectin is a heterodimeric protein complex which consists of two subunits including S100A8 and S100A9. This protein has a major role in different inflammatory disease and various types of cancers. In current study we aimed to evaluate the structural and thermodynamic changes of the subunits and the complex in presence of sodium and calcium ions using molecular dynamics (MD) simulation. Therefore, the residue interaction network (RIN) was visualized in Cytoscape program. In next step, to measure the binding free energy, the potential of mean force (PMF) method was performed. Finally, the molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method was applied as an effective tool to calculate the molecular model affinities. The MD simulation results of the subunits represented their structural changes in presence of Ca2+. Moreover, the RIN and Hydrogen bond analysis demonstrated that cluster interactions between Calprotectin subunits in presence of Ca2+ were greater in comparison with Na+. Our findings indicated that the binding free energy of the subunits in presence of Ca2+ was significantly greater than Na+. The results revealed that Ca2+ has the ability to induce structural changes in subunits in comparison with Na+ which lead to create stronger interactions between. Hence, studying the physical characteristics of the human proteins could be considered as a powerful tool in theranostics and drug design purposes.

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Assessing the capability ofin silicomutation protocols for predicting the finite temperature conformation of amino acids

Abstract: Single-point mutation protocols based on backbone-dependent rotamer libraries show the best performance in predicting equilibrium configurations from molecular dynamics simulations.

Cited by 19 publications

References 57 publications

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

Impact of Structural Observables From Simulations to Predict the Effect of Single-Point Mutations in MHC Class II Peptide Binders

In silico assessment of human Calprotectin subunits (S100A8/A9) in presence of sodium and calcium ions using Molecular Dynamics simulation approach

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