Parameterization and Application of the General Amber Force Field to Model Fluoro Substituted Furanose Moieties and Nucleosides

Abstract

Molecular mechanics force field calculations have historically shown significant limitations in modeling the energetic and conformational interconversions of highly substituted furanose rings. This is primarily due to the gauche effect that is not easily captured using pairwise energy potentials. In this study, we present a refinement to the set of torsional parameters in the General Amber Force Field (gaff) used to calculate the potential energy of mono, di-, and gem-fluorinated nucleosides. The parameters were optimized to reproduce the pseudorotation phase angle and relative energies of a diverse set of mono- and difluoro substituted furanose ring systems using quantum mechanics umbrella sampling techniques available in the IpolQ engine in the Amber suite of programs. The parameters were developed to be internally consistent with the gaff force field and the TIP3P water model. The new set of angle and dihedral parameters and partial charges were validated by comparing the calculated phase angle probability to those obtained from experimental nuclear magnetic resonance experiments.

Keywords: Amber; NMR; fluorinated; force field; furanose; molecular mechanics; nucleoside; sugar pucker.

Figure 1

Pucker profile of fluorinated sugars: (a) influence of fluorine on ring conformation. The ring pucker is pulled to the side of the most electronegative atom due to the gauche effect; (b) ring conformation, enzyme binding, and half-life of fluorinated Sal-AMS derivatives reported in [9].

Figure 2

Set of 24 test (T) furanose ring structures used to derive partial charges and parameterize torsional variables.

Figure 3

Comparison of molecular mechanics (MM) energies calculated using the gaff and sugar_mod force field parameters vs. quantum mechanics (QM) energies. The total sample size used was n = 47,596 structures. For clarity purposes, only the boundary of all data points is shown rather than individual data points. The red, solid and dashed, lines represent the energies calculated using the gaff force field parameters. The blue, solid and dashed, lines represent the energies calculated using the sugar_mod force field parameters.

Figure 4

Energy error statistics vs. sugar pucker phase angle (P) for (top) gaff force field and (bottom) sugar_mod force field parameters. The energy error was calculated as the difference between the average MM energy in 20 ns simulations at specific p values and the respective QM energy; both MM and QM simulations had structures with frozen sugar-heavy atoms. The boxplots show the statistical analysis for structures T = 1–24. On each distribution box, the red central mark indicates the average value (μ), the bottom and top edges of the box indicate one standard deviation (μ $\pm$ σ) and the whiskers extend to two standard deviations (μ $\pm$ 2σ).

Figure 5

Comparison of puckering between gaff and sugar_mod force fields for nucleosides 2–7: (a) Percent probability of phase angles for six fluorinated and hydroxylated Sal-AMS analogs calculated from unrestrained MD simulations using the IpolQ+sugar_mod (purple) and AM1-BCC + gaff parameters (brown). The light grey shaded region shows the North configuration region, i.e., $-90\le P\le 90$; (b) Comparison of total percent North (% N) probability for the six fluorinated and hydroxylated Sal-AMS analogs calculated from unrestrained MD simulations using the IpolQ + sugar_mod (blue) and AM1-BCC + gaff parameters (yellow) compared to the literature experimental NMR values [9].

Figure 6

Workflow used to calculate implicitly polarized and gas-phase partial charge sets for each molecule, and, the sugar_mod frcmod file containing the reparameterization of $V_n$ and $\gamma$ for the dihedrals of interest. The processes in blue have been explained in detail in Section 3.2.1 and Section 3.2.2 as well as Figure S4. The green and yellow files are force field and prepi files, respectively.