TKSA‐MC: A web server for rational mutation through the optimization of protein charge interactions

Contessoto, Vinícius G.; Oliveira, Vinícius Martins de; Fernandes, Bruno R.; Slade, Gabriel Gouvêa; Leite, Vitor Barbanti Pereira

doi:10.1002/prot.25599

Cited by 25 publications

(26 citation statements)

References 34 publications

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“…Further developments of xDLVO-CG and the inclusion of the solvent accessibility corrections, e.g. as available in the TKSA-MC server 96 or GBSA, 97 and other solvent effects, modulated by the change of the ionic strength, 98 are required to improve the quality of predictions and enable better correlations with the experimental observations.…”

Section: Application To Non-spherical Proteinsmentioning

confidence: 99%

A coarse-grained xDLVO model for colloidal protein–protein interactions

Pusara

Yamin

Wenzel

et al. 2021

Phys. Chem. Chem. Phys.

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Section: Application To Non-spherical Proteinsmentioning

confidence: 99%

A coarse-grained xDLVO model for colloidal protein–protein interactions

Pusara

Yamin

Wenzel

et al. 2021

Phys. Chem. Chem. Phys.

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“…It is assumed in the method that the unfolded state does not contribute to electrostatic interactions ( 35 ). The protonation states χ were calculated via Metropolis Monte Carlo algorithm, resulting in the TKSA-MC model ( 36 ).…”

Section: Methodsmentioning

confidence: 99%

A Dynamic Hydrophobic Core and Surface Salt Bridges Thermostabilize a Designed Three-Helix Bundle

Nguyen

Young

Slade

et al. 2019

Biophysical Journal

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Thermostable proteins are advantageous in industrial applications, as pharmaceuticals or biosensors, and as templates for directed evolution. As protein-design methodologies improve, bioengineers are able to design proteins to perform a desired function. Although many rationally designed proteins end up being thermostable, how to intentionally design de novo, thermostable proteins is less clear. UVF is a de novo-designed protein based on the backbone structure of the Engrailed homeodomain (EnHD) and is highly thermostable (T m > 99°C vs. 52°C for EnHD). Although most proteins generally have polar amino acids on their surfaces and hydrophobic amino acids buried in their cores, protein engineers followed this rule exactly when designing UVF. To investigate the contributions of the fully hydrophobic core versus the fully polar surface to UVF’s thermostability, we built two hybrid, chimeric proteins combining the sets of buried and surface residues from UVF and EnHD. Here, we determined a structural, dynamic, and thermodynamic explanation for UVF’s thermostability by performing 4 μ s of all-atom, explicit-solvent molecular dynamics simulations at 25 and 100°C, Tanford-Kirkwood solvent accessibility Monte Carlo electrostatic calculations, and a thermodynamic analysis of 40 temperature runs by the weighted-histogram analysis method of heavy-atom, structure-based models of UVF, EnHD, and both chimeric proteins. Our models showed that UVF was highly dynamic because of its fully hydrophobic core, leading to a smaller loss of entropy upon folding. The charged residues on its surface made favorable electrostatic interactions that contributed enthalpically to its thermostability. In the chimeric proteins, both the hydrophobic core and charged surface independently imparted thermostability.

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“…Using the PISA web server, we calculate the solvation free energy gain upon formation of the interface, interface area and number of potential hydrogen bonds and salt bridge [39]. Complementary to the PISA results, we applied the TKSA-MC [40] to estimate the contribution of electrostatic interaction to free energy for the polar residues, especially those that are localized in the interface of the dimer (Arg4, Glu14, Glu240 and Arg298). The TKSA-MC calculates protein charge-charge interactions via the Tanford-Kirkwood Surface Accessibility model with the Monte Carlo method for sampling different protein protonation states.…”

Section: Analysis Of Dimer Interfacementioning

confidence: 99%

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

Philot

Gasparini

Mattos

et al. 2021

Preprint

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In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.

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TKSA‐MC: A web server for rational mutation through the optimization of protein charge interactions

Cited by 25 publications

References 34 publications

A coarse-grained xDLVO model for colloidal protein–protein interactions

A coarse-grained xDLVO model for colloidal protein–protein interactions

A Dynamic Hydrophobic Core and Surface Salt Bridges Thermostabilize a Designed Three-Helix Bundle

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

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