The Static Modes: An alternative approach for the treatment of macro- and bio-molecular induced-fit flexibility

Abstract

We present a new competitive method for the atomic scale treatment of macromolecular flexibility called Static Mode method. This method is based on the "induced-fit" concept, i.e. it maps the intrinsic deformations of a macromolecule subject to diverse external excitations. The algorithm makes it possible to obtain a set of deformations, each one corresponding to a specific interaction on a specific molecular site, in terms of force constants contained in the energy model. In this frame, the docking problem can be expressed in terms of interaction sites between the two molecules, the molecular deformations being extracted from the pre-calculated Static Modes of each molecule. Some preliminary basic examples aimed at illustrating potential applications where macro- or bio-molecular flexibility is of key importance are given: flexibility inducing conformational changes in the case of furanose ring and flexibility for the characterization, including allostery, of poly(N-isopropylacrylamide)(P-NIPAM) active sites. We also discuss how this procedure allows "induced-fit" flexible molecular docking, beyond state-of-the-art semi-rigid methods.

Atomic-scale determination of DNA conformational response to strained furanose: a static mode approach

“…dedicated to study the flexible and rigid motifs in biomolecules, we have developed a new computing method: the static mode method (SM) (see Ref. 19 for more technical details).…”

“…18 These examples demonstrate that there is a major interest in understanding the basic mechanisms that are impacting DNA conformations enabling subsequent control of the DNA reactivity. Our purpose here is to shed light in these issues by using a static mode technique 19 that makes possible to map the DNA deformation response to specific and chosen external excitation with an atomic precision.…”

“…19 The overall goal of static modes is to provide a framework where full molecular flexibility can be obtained in a reasonable computer time. In this view, the static mode approach is an alternative to existing Molecular Dynamics techniques and Normal Mode Analysis based methods.…”

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

“…In a previous paper, we introduced a new methodology for the treatment of macromolecular flexibility: the static modes. 2 The idea of the static modes is to calculate the deformations of a molecule, in terms of atomic displacements, due to an external excitation, which can be mechanical, electrical or resulting because of its interaction with another molecule. In this latter case, the new methodology is very useful for the understanding and prediction of biological processes, and more precisely for the description of molecular docking procedures.…”

“…A binding site has been identified which is situated in the 16 first amino acid fragment. 13,14 This truncated peptide, noted Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), also tends to form b-sheet rich fibrils in the presence of metallic ions. In this paper, our goal is to use the static modes to measure the influence of a metallic ion on the Ab(1-16) peptide.…”