Effects of Lysine Substitution on Stability of Polyalanine α Helix

Ponomarev, Sergei Y.; Sa, Qina; Kaminski, George A.

doi:10.1021/ct300492n

Cited by 8 publications

(21 citation statements)

References 19 publications

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“…12 These parametrizations were carried out using the structures shown in Figure 6 for the charged termini and analogous ones for the electrostatically neutral termini. These fragments correspond to the termini with an adjacent alanine residue.…”

Section: Resultsmentioning

confidence: 99%

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POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

Ponomarev

Sigalovsky

et al. 2014

J. Chem. Theory Comput.

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Previously, we reported development of a fast polarizable force field and software named POSSIM (POlarizable Simulations with Second order Interaction Model). The second-order approximation permits the speed up of the polarizable component of the calculations by ca. an order of magnitude. We have now expanded the POSSIM framework to include a complete polarizable force field for proteins. Most of the parameter fitting was done to high-level quantum mechanical data. Conformational geometries and energies for dipeptides have been reproduced within average errors of ca. 0.5 kcal/mol for energies of the conformers (for the electrostatically neutral residues) and 9.7° for key dihedral angles. We have also validated this force field by running Monte Carlo simulations of collagen-like proteins in water. The resulting geometries were within 0.94 Å root-mean-square deviation (RMSD) from the experimental data. We have performed additional validation by studying conformational properties of three oligopeptides relevant in the context of N-glycoprotein secondary structure. These systems have been previously studied with combined experimental and computational methods, and both POSSIM and benchmark OPLS-AA simulations that we carried out produced geometries within ca. 0.9 Å RMSD of the literature structures. Thus, the performance of POSSIM in reproducing the structures is comparable with that of the widely used OPLS-AA force field. Furthermore, our fitting of the force field parameters for peptides and proteins has been streamlined compared with the previous generation of the complete polarizable force field and relied more on transferability of parameters for nonbonded interactions (including the electrostatic component). The resulting deviations from the quantum mechanical data are similar to those achieved with the previous generation; thus, the technique is robust, and the parameters are transferable. At the same time, the number of parameters used in this work was noticeably smaller than that of the previous generation of our complete polarizable force field for proteins; thus, the transferability of this set can be expected to be greater, and the danger of force field fitting artifacts is lower. Therefore, we believe that this force field can be successfully applied in a wide variety of applications to proteins and protein–ligand complexes.

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Section: Resultsmentioning

confidence: 99%

“…12 Following this success, we have now extended the development of the POSSIM force field to the complete set of amino acids and applied it in test simulations of a collagen-like protein. The results are presented in this article.…”

Section: Introductionmentioning

confidence: 99%

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

Ponomarev

Sigalovsky

et al. 2014

J. Chem. Theory Comput.

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“…Most of the POSSIM parameters for the p K a calculations of acid and basic residues of OMTKY3 protein were adopted from previous works . New parameters were produced whenever they did not exist before.…”

Section: Resultsmentioning

confidence: 99%

“…These calculations are done with modified POSSIM software suite including revised FB continuum solvation model. POSSIM force field was used for simulating the solutes in the p K a calculations of both the acid and the base residues of OMTKY3 protein. Values of the hydration parameters of the small molecules were produced by fitting to the experimental or quantum mechanical solvation energies of these systems.…”

Section: Resultsmentioning

confidence: 99%

Using polarizable POSSIM force field and fuzzy‐border continuum solvent model to calculate pK_a shifts of protein residues

Sharma

Kaminski

2016

J Comput Chem

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Our Fuzzy-Border (FB) continuum solvent model has been extended and modified to produce hydration parameters for small molecules using POlarizable Simulations Second-order Interaction Model (POSSIM) framework with an average error of 0.136 kcal/mol. It was then used to compute pKa shifts for carboxylic and basic residues of the turkey ovomucoid third domain (OMTKY3) protein. The average unsigned errors in the acid and base pKa values were 0.37 and 0.4 pH units, respectively, versus 0.58 and 0.7 pH units as calculated with a previous version of polarizable protein force field and Poisson Boltzmann continuum solvent. This POSSIM/FB result is produced with explicit refitting of the hydration parameters to the pKa values of the carboxylic and basic residues of the OMTKY3 protein, thus the values of the acidity constants can be viewed as additional fitting target data. In addition to calculating pKa shifts for the OMTKY3 residues, we have studied aspartic acid residues of Rnase Sa. This was done without any further refitting of the parameters and agreement with the experimental pKa values is within an average unsigned error of 0.65 pH units. This result included the Asp79 residue that is buried and thus has a high experimental pKa value of 7.37 units. Thus, the presented model is capable or reproducing pKa results for residues in an environment that is significantly different from the solvated protein surface used in the fitting. Therefore, the POSSIM force field and the Fuzzy Border continuum solvent parameters have been demonstrated to be sufficiently robust and transferable.

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“…The formalisms of the fixed‐charges OPLS‐AA and our polarizable POSSIM force fields can be described briefly as follows. The total energy E tot is found as a sum of the electrostatic interactions E electrostatic , the van‐der‐Waals energy E vdW , harmonic bond stretching and angle bending E stretch and E bend , and the torsional energy E torsion :

E_{tot} = E_{electrostatic} + E_{vdW} + E_{stretch} + E_{bend} + E_{torsion}

…”

Section: Methodsmentioning

confidence: 99%

Developing multisite empirical force field models for Pt(II) and cisplatin

Cvitkovic

Kaminski²

2016

J. Comput. Chem.

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We have developed empirical force field parameters for Pt(II) and cisplatin. Two force field frameworks were employed – modified OPLS-AA and our second-order polarizable POSSIM. A seven-site model was used for the Pt(II) ion. The goal was to create transferable parameter sets compatible with the force field models for proteins and general organic compounds. A number of properties of the Pt(II) ion and its coordination compounds have been considered, including geometries and energies of the complexes, hydration free energy, and radial distribution functions in water. Comparison has been made with experimental and quantum mechanical results. We have demonstrated that both versions are generally capable of reproducing key properties of the system, but the second-order polarizable POSSIM formalism permits more accurate quantitative results to be obtained. For example, the energy of formation of cisplatin as calculated with the modified OPLS-AA exhibited an error of 9.9%, while the POSSIM error for the same quantity was 6.2%. The produced parameter sets are transferable and suitable to be employed in protein-metal binding simulations in which position or even coordination of the ion does not have to be constrained using preexisting knowledge.

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Effects of Lysine Substitution on Stability of Polyalanine α Helix

Cited by 8 publications

References 19 publications

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

Using polarizable POSSIM force field and fuzzy‐border continuum solvent model to calculate pK_a shifts of protein residues

Developing multisite empirical force field models for Pt(II) and cisplatin

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Effects of Lysine Substitution on Stability of Polyalanine α Helix

Cited by 8 publications

References 19 publications

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins

Using polarizable POSSIM force field and fuzzy‐border continuum solvent model to calculate pKa shifts of protein residues

Developing multisite empirical force field models for Pt(II) and cisplatin

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Using polarizable POSSIM force field and fuzzy‐border continuum solvent model to calculate pK_a shifts of protein residues