Constrained Unfolding of a Helical Peptide: Implicit versus Explicit Solvents

Abstract

Steered Molecular Dynamics (SMD) has been seen to provide the potential of mean force (PMF) along a peptide unfolding pathway effectively but at significant computational cost, particularly in all-atom solvents. Adaptive steered molecular dynamics (ASMD) has been seen to provide a significant computational advantage by limiting the spread of the trajectories in a staged approach. The contraction of the trajectories at the end of each stage can be performed by taking a structure whose nonequilibrium work is closest to the Jarzynski average (in naive ASMD) or by relaxing the trajectories under a no-work condition (in full-relaxation ASMD—namely, FR-ASMD). Both approaches have been used to determine the energetics and hydrogen-bonding structure along the pathway for unfolding of a benchmark peptide initially constrained as an α-helix in a water environment. The energetics are quite different to those in vacuum, but are found to be similar between implicit and explicit solvents. Surprisingly, the hydrogen-bonding pathways are also similar in the implicit and explicit solvents despite the fact that the solvent contact plays an important role in opening the helix.

Thermodynamics, morphology, and kinetics of early-stage self-assembly of π-conjugated oligopeptides

“…[44] The Generalised Born model has been known to overestimate the stability of inter-residue interactions, [45][46][47] but has also been shown to accurately treat solvent effects in simulating proteins [48][49][50] even when such proteins are stabilised by solvent effects. [51,52] Accordingly, we make use of this implicit solvent model in order to reach the requisite time and length scales to observe peptide self-assembly, but -as detailed in Section 3.3 -we employed a rescaled version of the CHARMM27 force field in which the Lennard-Jones and Coulomb interactions were scaled such that intramolecular free energy landscapes for both the peptide monomer and the dimerisation free energy pathway in implicit solvent reproduced those computed under explicit solvation. Simulations were otherwise conducted in the same manner as the explicit-solvent systems except that LennardJones interactions were shifted smoothly to zero at a cutoff of 3.4 nm, and electrostatics were also treated by shifting to zero at a cutoff of 3.4 nm.…”

The relative stability of trpzip1 and its mutants determined by computation and experiment

“…Observables, such as hydrogen-bonding, are in principle more sensitive to the errors of naive ASMD because they depend on the structure of the particular structures sampled in the ensemble. The fact that hydrogen-bonding converged more readily in the smaller peptides used to benchmark our earlier work 17,24,25 is indicative that for such peptides, that the PMF is determined by a single dominant pathway in the nonequilibrium ensemble. In the present set of peptides, the hydrogen bond proles exhibit discontinuities at junctures between stages.…”

“…The Adaptive Steered Molecular Dynamics (ASMD) method, which was previously developed 16 and benchmarked for vacuum, 24 implicit solvent, 25 and explicit solvent 17 conditions for the a-helical peptide Ala 10 , was used for calculating the PMFs of the six b-hairpin peptides. This method overcomes the sampling problems previously observed in standard Steered Molecular Dynamics (SMD) simulations.…”

Exploring the structure characteristics and major channels of cytochrome P450 2A6, 2A13, and 2E1 with pilocarpine

“…In the present study, ASMD simulations which were performed using AMBER12 can provide a more detailed mapping of the force profiles along the reaction coordinate . In ASMD, the predetermined reaction coordinate is divided into segments, commonly referred to as stages, within which SMD is performed and the Jarzynski average (JA) is computed throughout the stage.…”