The electrostatic probe: a tool for the investigation of the Aβ(1–16) peptide deformations using the static modes

Abstract

We investigate the conformational changes of the Amyloid β(1-16) peptide induced by moving Zn(2+) ions in the solvent, which we call the electrostatic probe. We use our recently developed approach of static modes which allows treating the flexibility of biological molecules at the atomic scale. Starting from an experimental apostructure, we find that several ion impacts allow the transition of the peptide toward its folded conformation, observed experimentally in the presence of Zn(2+) ions. This result shows the ability of our model and its associated software tool to describe properly the conformational changes and opens a new path toward the molecule/molecule docking problem.

Toward in Silico Biomolecular Manipulation through Static Modes: Atomic Scale Characterization of HIV-1 Protease Flexibility

“…Conformational change can be performed exploring the pathway built through a succession of deformation/relaxation steps, in which static modes will be recalculated when necessary. A similar strategy was proposed and discussed in a previous work to investigate the conformational changes of the amyloid β(1–16) peptide induced by Zn 2+ ions …”

“…In this paper, we demonstrate that our static mode approach, after being presented and exposed on various molecular targets, ,,− enables concentrating all the information required for studying biomechanical properties at large within a costless framework in terms of calculation time and an infinite capability of considering biomolecular excitation. Through this study, thanks to the static mode method, we have rapidly collected many essential properties of a model system, namely, HIV-1 PR, properties already derived from multiple experimental or computational methods during the last 20 years.…”

“…Anharmonic effects could be introduced using matrices of higher order. Details about the method have already been published and partial results on several biomolecules reported. − In particular, we have successfully quantitatively correlated results to experiments, and probed active site stability and mutation effects on enzymatic activity . The static mode method allows calculating all the deformations of a molecule submitted to elementary external excitations.…”

“…For this reason, HIV-1 PR constitutes a good model system making it possible for us to validate the predictive nature of our method as well as to illustrate its potential beyond state of the art. In particular, we show how our static modes − can be post-treated in an interactive manner to design complex excitations. Through manipulation tools, an operator can design and evaluate an infinite set of single to multiple excitations, constraints, or interactions with no further computational cost.…”

Enhancing DFT-based energy landscape exploration by coupling quantum mechanics and static modes

“…Such perturbations can be designed by the user to address specific questions, as discussed later. In this manner, the SM approach was validated and applied to various biological systems, SM being used to simulate protein folding upon electrostatic interactions, 9 active site stability upon mutations, 10 conformational change upon ligand binding, 11 and molecular properties upon functionalization, 12 to name but a few. Through these different cases, the SM predictive nature has been consolidated and shown to be associated with a very low computational cost, offering a versatile range of possibilities.…”