Polarizable simulations with second order interaction model (POSSIM) force field: Developing parameters for protein side‐chain analogues

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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“…14 The average unsigned error of the three calculated three-body energies for pyrrole was 0.184 kcal/mol.…”

Section: Resultsmentioning

confidence: 94%

“…14 In these instances, parametrization consisted of fitting torsional parameters for the χ 1 , χ 2 , etc. dihedrals of the side chains.…”

Section: Methodsmentioning

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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“…The non-bonded part of these sets were taken from the POSSIM CH 3 COOH, CH 3 COO − , CH 3 NH 2 systems 18 and the CH 3 NH 3 + cation parameter set developed in the course of this work. The torsional component of the parameters was obtained by fitting the POSSIM against the LMP2/cc-pVTZ(−f) quantum mechanical energies for the rotamers having different angles for the terminal groups (–COOH, –COO − , –NH 2 and –NH 3 + ).…”

Section: Methodsmentioning

confidence: 99%

Effects of Lysine Substitution on Stability of Polyalanine α Helix

Ponomarev

Kaminski

2012

J. Chem. Theory Comput.

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We have studied stability of polyalanine alpha-helices with lysine residues added at C-and N-termini in gas-phase and aqueous solution. Monte Carlo simulations with the fixed-charges OPLS-AA and our polarizable POSSIM force fields were carried out. The results of the simulations confirm previously observed phenomena of the helix being stable with the LYS residue on the C-terminus and losing its helical structure if the charged LYS residue is located at the N-terminus of the polypeptide in gas-hase. Both OPLS-AA and POSSIM force fields performed essentially similarly, thus validity of the both for reproducing and predicting structures of such polypeptides has been confirmed. We have also studied the effect of replacing the normal N- and C-termini with methyl capping (this approach is often used in computational studies). Our results have demonstrated that the structure and stability of the polypeptides do not depend significantly on such a substitution although details of the resulting structure may change. The liquid-state simulations produced stable alpha-helixes regardless of the position of the protonated lysine residue. Overall, we have validated our polarizable POSSIM force field and the techniques used in the simulations, since the change of the helix structure as a function of the position of the LYS residue depends on a fine balance of energy contributions, and our methodology reproduced this balance well.

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“…26,27 Even for gas phase dimers or oligomers, electronic polarization contributes significantly to the interaction energy, 9,28,29 and such reference data are therefore often used to validate PFFs. 18,21,[30][31][32] For homogeneous systems, PFFs also improve the correspondence between simulated and experimental data. For example, PFF simulations of organic or ionic liquids showed an improved correspondence of thermodynamic and structural properties with experiment, while also reproducing gas-phase dimer properties.…”

Section: Introductionmentioning

confidence: 91%

“…For example, PFF simulations of organic or ionic liquids showed an improved correspondence of thermodynamic and structural properties with experiment, while also reproducing gas-phase dimer properties. 24,30,31,[33][34][35][36][37][38][39][40] In the field of materials science, PFFs are gaining attention as well, e.g., a polarizable Al-O potential was recently proposed that can reproduce crystal energies, lattice constants, and deformation energies of different Al x O y crystal phases. 41 Another nice example is a LiI PFF that was fitted to ab initio reference data and that reproduces properties of both the liquid and crystal phases.…”

Section: Introductionmentioning

confidence: 99%

Direct computation of parameters for accurate polarizable force fields

Verstraelen

Vandenbrande

Ayers

2014

The Journal of Chemical Physics

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We present an improved electronic linear response model to incorporate polarization and charge-transfer effects in polarizable force fields. This model is a generalization of the Atom-Condensed Kohn-Sham Density Functional Theory (DFT), approximated to second order (ACKS2): it can now be defined with any underlying variational theory (next to KS-DFT) and it can include atomic multipoles and off-center basis functions. Parameters in this model are computed efficiently as expectation values of an electronic wavefunction, obviating the need for their calibration, regularization, and manual tuning. In the limit of a complete density and potential basis set in the ACKS2 model, the linear response properties of the underlying theory for a given molecular geometry are reproduced exactly. A numerical validation with a test set of 110 molecules shows that very accurate models can already be obtained with fluctuating charges and dipoles. These features greatly facilitate the development of polarizable force fields.

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Polarizable simulations with second order interaction model (POSSIM) force field: Developing parameters for protein side‐chain analogues

Cited by 11 publications

References 29 publications

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

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

Effects of Lysine Substitution on Stability of Polyalanine α Helix

Direct computation of parameters for accurate polarizable force fields

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