Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for alanine peptides and protein backbone

Abstract

A previously introduced POSSIM (POlarizable Simulations with Second order Interaction Model) force field has been extended to include parameters for alanine peptides and protein backbones. New features were introduced into the fitting protocol, as compared to the previous generation of the polarizable force field for proteins. A reduced amount of quantum mechanical data was employed in fitting the electrostatic parameters. Transferability of the electrostatics between our recently developed NMA model and the protein backbone was confirmed. Binding energy and geometry for complexes of alanine dipeptide with a water molecule were estimated and found in a good agreement with high-level quantum mechanical results (for example, the intermolecular distances agreeing within ca. 0.06Å). Following the previously devised procedure, we calculated average errors in alanine di- and tetra-peptide conformational energies and backbone angles and found the agreement to be adequate (for example, the alanine tetrapeptide extended-globular conformational energy gap was calculated to be 3.09 kcal/mol quantim mechanically and 3.14 kcal/mol with the POSSIM force field). However, we have now also included simulation of a simple alpha-helix in both gas-phase and water as the ultimate test of the backbone conformational behavior. The resulting alanine and protein backbone force field is currently being employed in further development of the POSSIM fast polarizable force field for proteins.

Figure 1

Protein backbone angles φ and ψ shown in the alanine dipeptide molecule.

Figure 2

Torsional fitting subspace, for the alanine dipeptide φ/ψ potential energy surface. Such crosses were centered at each of the six minima and each arm contained four fitting points (here some crosses and points are omitted for the sake of clarity).

Figure 3

LMP2/cc-pVTZ(-f) geometry of the extended alanine tetrapeptide conformation.

Figure 4

LMP2/cc-pVTZ(-f) geometry of the globular alanine tetrapeptide conformation.

Figure 4

Alanine dipeptide hydrogen bonded complex with a water molecule, structure A.

Figure 5

Alanine dipeptide hydrogen bonded complex with a water molecule, structure B.

Figure 6

Average φ angles in α-helix gas-phase simulations vs. the simulation length.

Figure 7

Average ψ angles in α-helix gas-phase simulations vs. the simulation length.

Figure 8

Structure of the ala-13 a-helix simulated with OPLS in gas-phase, after 19 × 10⁶ Monte Carlo configurations.

Figure 9

Structure of the ala-13 a-helix simulated with POSSIM, version tors.1, in gas-phase, after 19 × 10⁶ Monte Carlo configurations.

Figure 10

Structure of the ala-13 a-helix simulated with POSSIM, version tors.final in gas-phase, after 19 × 10⁶ Monte Carlo configurations.

Figure 11

Average φ angles in α-helix simulations in aqueous solution vs. the simulation length, in millions of Monte Carlo configurations.

Figure 12

Average ψ angles in α-helix simulations is aqueous solution vs. the simulation length, in millions of Monte Carlo configurations.

Figure 13

Structure of the ala-13 a-helix simulated with OPLS, in aqueous solution, after 25 × 10⁶ Monte Carlo configurations. Water molecules are not shown for the sake of clarity.

Figure 14

Structure of the ala-13 a-helix simulated with POSSIM, version tors.1, in aqueous solution, after 25 × 10⁶ Monte Carlo configurations. Water molecules are not shown for the sake of clarity.

Figure 15

Structure of the ala-13 a-helix simulated with POSSIM, version tors.final, in aqueous solution, after 25 × 10⁶ Monte Carlo configurations. Water molecules are removed for clarity.