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

Li X, Ponomarev SY, Sigalovsky DL, Cvitkovic JP, Kaminski GA - J Chem Theory Comput (2014)

Bottom Line: 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.Therefore, we believe that this force field can be successfully applied in a wide variety of applications to proteins and protein-ligand complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute , Worcester, Massachusetts 01609, United States.

ABSTRACT
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.

No MeSH data available.


Dipolar probes used in calculating three-bodyenergy of the methylguanidinium ion. Symbols “P” and “N” denote the positiveand negative point charges, respectively.
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fig2: Dipolar probes used in calculating three-bodyenergy of the methylguanidinium ion. Symbols “P” and “N” denote the positiveand negative point charges, respectively.

Mentions: Pairs of these probes were used in calculating three-bodyenergies,and values of atomic polarizabilities were fitted to reproduce thesethree-body energy values. Five of the probes have their negative chargespointed toward the five polar hydrogen atoms of the cation. The othertwo have their positive point charges at hydrogen bonding distancesfrom the −NH2 nitrogens, as can be seen from Figure 2. Therefore, there is a total of twenty-one possiblethree-body energies for the methylguanidinium cation. The averageabsolute error in the three-body energies of methylguanidinium wasonly 0.118 kcal/mol, which is a great result given that there are21 three-body values.


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

Li X, Ponomarev SY, Sigalovsky DL, Cvitkovic JP, Kaminski GA - J Chem Theory Comput (2014)

Dipolar probes used in calculating three-bodyenergy of the methylguanidinium ion. Symbols “P” and “N” denote the positiveand negative point charges, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230370&req=5

fig2: Dipolar probes used in calculating three-bodyenergy of the methylguanidinium ion. Symbols “P” and “N” denote the positiveand negative point charges, respectively.
Mentions: Pairs of these probes were used in calculating three-bodyenergies,and values of atomic polarizabilities were fitted to reproduce thesethree-body energy values. Five of the probes have their negative chargespointed toward the five polar hydrogen atoms of the cation. The othertwo have their positive point charges at hydrogen bonding distancesfrom the −NH2 nitrogens, as can be seen from Figure 2. Therefore, there is a total of twenty-one possiblethree-body energies for the methylguanidinium cation. The averageabsolute error in the three-body energies of methylguanidinium wasonly 0.118 kcal/mol, which is a great result given that there are21 three-body values.

Bottom Line: 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.Therefore, we believe that this force field can be successfully applied in a wide variety of applications to proteins and protein-ligand complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute , Worcester, Massachusetts 01609, United States.

ABSTRACT
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.

No MeSH data available.