ARTIST: An activated method in internal coordinate space for sampling protein energy landscapes

Abstract

We present the first applications of an activated method in internal coordinate space for sampling all-atom protein conformations, the activation-relaxation technique for internal coordinate space trajectories (ARTIST). This method differs from all previous internal coordinate-based studies aimed at folding or refining protein structures in that conformational changes result from identifying and crossing well-defined saddle points connecting energy minima. Our simulations of four model proteins containing between 4 and 47 amino acids indicate that this method is efficient for exploring conformational space in both sparsely and densely packed environments, and offers new perspectives for applications ranging from computeraided drug design to supramolecular assembly. Proteins 2006;63:967-975.

Following atomistic kinetics on experimental timescales with the kinetic Activation–Relaxation Technique

“…Such an approach was used, for example, to study the energy landscape of crystalline materials with defects [32,34,35] as well as that of amorphous silicon and glasses [37,[39][40][41][42][43]. Coupled with a Metropolis accept/reject criterion based on the energy-di↵erence between the final and the initial minimum in an event, ART nouveau was also used extensively to generate protein folding and aggregation trajectories [44][45][46][47][48] and identify relaxation pathways in complex materials [36,38,49,50]. …”

A Local Rigid Body Framework for Global Optimization of Biomolecules

“…Different trial moves, such as short molecular dynamics runs, random displacements, or activated events 27 either in Cartesian or internal coordinates, could also be used and combined. For the dihedral moves, a number of backbone dihedral angles are selected and twisted in the manner described in reference.…”

Sampling small-scale and large-scale conformational changes in proteins and molecular complexes

“…͑i͒ Leave the present local minimum along a random direction and find a negative eigenvalue in the Hessian matrix using the Lanczos technique. 22 To control or limit atomic collisions, it is common to use soft-core Lennard-Jones potentials or reduced representations. ͑iii͒ Push the system over the saddle point and minimize the conformation in the new local minimum.…”

“…͑iii͒ Push the system over the saddle point and minimize the conformation in the new local minimum. 23 and in the first version of ARTIST, 22 by adding an adaptive approach to offer a better relaxation in the hyperplane perpendicular to the direction of activation, while moving along the direction of negative curvature with an adaptive step to avoid head-on collisions between atoms. Since ARTIST moves from local minimum to local minimum, the Metropolis temperature cannot be simply related to the physical temperature.…”

“…22 ART-IST is the result of merging two programs: LIGAND, an internal coordinate minimization program, which defines the internal degrees of freedom and the intermolecular rotations and translations, 22 and ART NOUVEAU, an activationrelaxation algorithm. Along this idea, we recently combined the use of internal coordinates with a first-order saddle point search method and proposed the activation-relaxation technique for internal coordinate space trajectories ͑ARTIST͒ which samples the energy landscape by identifying welldefined transition states connecting two local minima.…”