Secondary structure bias in generalized Born solvent models: comparison of conformational ensembles and free energy of solvent polarization from explicit and implicit solvation

Abstract

The effects of the use of three generalized Born (GB) implicit solvent models on the thermodynamics of a simple polyalanine peptide are studied via comparing several hundred nanoseconds of well-converged replica exchange molecular dynamics (REMD) simulations using explicit TIP3P solvent to REMD simulations with the GB solvent models. It is found that when compared to REMD simulations using TIP3P the GB REMD simulations contain significant differences in secondary structure populations, most notably an overabundance of alpha-helical secondary structure. This discrepancy is explored via comparison of the differences in the electrostatic component of the free energy of solvation (DeltaDeltaG(pol)) between TIP3P (via thermodynamic Integration calculations), the GB models, and an implicit solvent model based on the Poisson equation (PE). The electrostatic components of the solvation free energies are calculated using each solvent model for four representative conformations of Ala10. Since the PE model is found to have the best performance with respect to reproducing TIP3P DeltaDeltaG(pol) values, effective Born radii from the GB models are compared to effective Born radii calculated with PE (so-called perfect radii), and significant and numerous deviations in GB radii from perfect radii are found in all GB models. The effect of these deviations on the solvation free energy is discussed, and it is shown that even when perfect radii are used the agreement of GB with TIP3P DeltaDeltaG(pol) values does not improve. This suggests a limit to the optimization of the effective Born radius calculation and that future efforts to improve the accuracy of GB models must extend beyond such optimizations.

Figure 1

Cartoon represenations of the four conformations of Ala10 used in this study. Picture generated with VMD 1.8.4.

Figure 2

Secondary structure and local conformational propensities for each residue of Ala10 from unrestrained REMD simulations using various solvent models at 300.0 K. Residues 1 and 12 are the acetyl and amide N- and C-caps respectively. Error bars are calculated as half the difference of values reported from two independent simulations with the given solvent model, using different initial coordinates.

Figure 3

Plot of fractional α-helical structure (%α/[100−%α]) obtained from DSSP analysis of REMD simulations with various solvent models versus the corresponding ΔΔG_Pol value between the PP2 and Alpha conformations. The data points from right to left are for the GBNeck, TIP3P, GBOBC, and GBHCT solvent models. As the solvation free energy gap in the given solvent model between the PP2 and Alpha structures decreases, the amount of α-helical structure in simulations with that model increases.