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 ns 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 over-abundance of α-helical secondary structure. This discrepancy is explored via comparison of the differences in the electrostatic component of the free energy of solvation (ΔΔG Pol ) between TIP3P (via Thermodynamic Integration calculations), the GB models, and an implicit solvent model based on the Poisson Equation (PE). The electrostatic component of the solvation free energies are calculated using each solvent model for four representative conformations of Ala10. Since PE is found to have the best performance with respect to reproducing TIP3P ΔΔG 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 ΔΔG 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 must extend beyond such optimizations.

Mixed quantum-classical dynamics of an amide-I vibrational excitation in a proteinα-helix

“…7,15,17 We chose helical deca-alanine as a test case due to its simple repeating sequence, and the fact that it has been the subject of previous studies and is known to display some level of helicity. 18 We first created helical deca-alanine ͑Ace-Ala 10 -NH 2 ͒ by setting all / dihedral angles to −57.8°/ −47.0°. The leap and antechamber modules of the MD program AMBER9 ͑Ref.…”

Evaluating force field accuracy with long-time simulations of a β-hairpin tryptophan zipper peptide

“…This provides a potential contrast with a recent computational study of trpzip2 that used the same force field and TIP3P explicit solvent, 16 which found a folding free energy close to −0.5 kcal/mol at 273 K. However, this divergence is unsurprising, given that previous studies comparing implicit and explicit solvent have shown that GB models tend to overstabilize α-helical conformations. [40][41][42] As indicated by the potential of mean force versus D rms at 293 K in Fig. 2, this effect need not be large to destabilize the native state in the context of ff99SB.…”

A strategy for reducing gross errors in the generalized Born models of implicit solvation

“…Despite its documented successes, there is a clear sense in the modeling community that the canonical GB approximation is still a much less faithful representation of reality than the standard numerical PE (PB) implicit solvation treatment, 50 let alone the more fundamental explicit solvation framework. 27,[50][51][52] For example, it appears that the GB does not have the right balance between intrasolute and solvent-solute charge-charge interactions, resulting in overstabilization of salt bridges; [52][53][54] erroneous salt bridges appear to be a generic property of various GB flavors.…”

“…27,[50][51][52] For example, it appears that the GB does not have the right balance between intrasolute and solvent-solute charge-charge interactions, resulting in overstabilization of salt bridges; [52][53][54] erroneous salt bridges appear to be a generic property of various GB flavors. 51 And while some of the discrepancies (relative to the explicit solvent results) are already present at the continuum solvent (PE) level, the rest come directly from the approximations of the PE → GB step.…”