Structure and Dynamics of End-to-End Loop Formation of the Penta-Peptide Cys-Ala-Gly-Gln-Trp in Implicit Solvents

Abstract

To investigate the effects of implicit solvents on peptide structure and dynamics, we performed extensive molecular dynamics simulations on the penta-peptide Cys-Ala-Gly-Gln-Trp. Two different implicit solvent models based on the CHARMM22 all-atom force field were used. Structural properties of the peptide such as distributions of end-to-end distances and dihedral angles obtained from molecular dynamics simulations with implicit solvent models were in a good agreement with those obtained from a previous explicit solvent simulation using the same force field. Representative structures observed in explicit solvent were sampled by implicit solvent models but with different relative probabilities. However, we observed significant differences in dynamical properties in explicit and implicit solvent models when we used traditional methods for the temperature control, such as Nosé-Hoover or Berendsen thermostats. The explicitly solvated peptide displayed the slowest dynamics in both end-to-end contact formation and intrinsic diffusive motion of end-to-end distances. A closer agreement between implicit and explicit solvated peptide dynamics was observed when Langevin dynamics with a friction coefficient of 10 ps -1 was used to maintain the temperature of the systems.

Free energies of solvation in the context of protein folding: Implications for implicit and explicit solvent models

“…This brings us to the second assumption, that the implicit solvent models provide a better description of solvation effects in the context of protein folding, which, based on our findings, would imply that the TIP3P model is overstabilizing the unfolded state relative to the folded state. Many studies exist showing that implicit solvent models are capable of accurate prediction of experimental results, especially the previously mentioned small molecule hydration free energy predictions and correspondence of the folded state with the lowest energy state . They have also been successfully used in applications including modeling and design of large biomolecules (an EEF1‐based implicit solvent model is used by Rosetta), prediction of changes in free energies of folding upon single residue mutations, and prediction of ligand binding energies .…”

“…Many studies exist showing that implicit solvent models are capable of accurate prediction of experimental results, especially the previously mentioned small molecule hydration free energy predictions [49] and correspondence of the folded state with the lowest energy state. [50,52,[54][55][56][57] They have also been successfully used in applications including modeling and design of large biomolecules (an EEF1-based implicit solvent model is used by Rosetta [137,138] ), prediction of changes in free energies of folding upon single residue mutations, [139] and prediction of ligand binding energies. [140] Problems with TIP3P and similar water models have been noted in previous studies, and improvements explored.…”

“…Instead of using structural measures to indirectly evaluate the implicit solvent models, we sought to use an approach that directly compares values. As recent protein folding simulations in explicit and implicit solvents accurately reproduced conformations of the folded state of small proteins, we wondered whether changes in upon folding provided by most commonly used implicit solvent models are consistent with the solvation effects that explicit water models provide. Therefore, using trajectories resultant from explicit water simulations, we derived relative values implied by the simulations and compared them with values provided by implicit solvent models.…”

Molecular dynamics simulations of protein dynamics and their relevance to drug discovery

“…Despite the great promise of the latest generation GB models, there has been no systematic study of the influence of using an implicit solvent model on protein dynamics and there have been indicates that the GB models are still lacking the accuracy needed for precise analysis of conformations, especially of protein complexes [36-38]. …”

Investigating the glass transition temperature at the atom-level in select model polyamides: A molecular dynamics study

“…To access local rigidity, we calculate the free energy or potential-of-mean force [33,34] associated with these rotations around a single C-C bond in the bis-cyclohexyl ring and bis-phenyl ring moieties present in the cycloaliphatic and aromatic polyamide, respectively. This quantity can be calculated through )) (…”