MinActionPath: maximum likelihood trajectory for large-scale structural transitions in a coarse-grained locally harmonic energy landscape

Abstract

The non-linear problem of simulating the structural transition between two known forms of a macromolecule still remains a challenge in structural biology. The problem is usually addressed in an approximate way using ‘morphing’ techniques, which are linear interpolations of either the Cartesian or the internal coordinates between the initial and end states, followed by energy minimization. Here we describe a web tool that implements a new method to calculate the most probable trajectory that is exact for harmonic potentials; as an illustration of the method, the classical Calpha-based Elastic Network Model (ENM) is used both for the initial and the final states but other variants of the ENM are also possible. The Langevin equation under this potential is solved analytically using the Onsager and Machlup action minimization formalism on each side of the transition, thus replacing the original non-linear problem by a pair of linear differential equations joined by a non-linear boundary matching condition. The crossover between the two multidimensional energy curves around each state is found numerically using an iterative approach, producing the most probable trajectory and fully characterizing the transition state and its energy. Jobs calculating such trajectories can be submitted on-line at: http://lorentz.dynstr.pasteur.fr/joel/index.php.

Enhanced Amino Acid Selection in Fully Evolved Tryptophanyl-tRNA Synthetase, Relative to Its Urzyme, Requires Domain Motion Sensed by the D1 Switch, a Remote Dynamic Packing Motif

“…We used the recently described algorithm POVME (21) to assess the tryptophan binding pocket volumes (287 Å 3 , 102 Å 3 , and 92 Å 3 ) of these three states. These substantial changes suggest a possible mechanism to account for the association of specific substrate selection with domain movement, as well as the unique role of Ile-4: control over the tryptophan binding pocket volume by domain movement (10,17). 4 These structural sequences illustrate semi-quantitatively (e.g.…”

“…Moreover, we illustrate the sequential structural changes involved in long range coupling by constructing a minimum action path (10) to connect the three crystal structures that represent stable states along the path. Repacking of the four mutated D1 Switch residues occurs twice, coincident with the transition states for induced-fit and catalysis.…”

Sampling large conformational transitions: adenylate kinase as a testing ground

“…The simulation of conformational transitions can be roughly subdivided into three distinct, but interdependent objectives: (1) accurately simulate conformational transition ensembles, (2) determine underlying free energy landscapes, and (3) predict transition probabilities and rates. A wide range of computational approaches to simulate rare transition events have been proposed [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24], which all, however, necessitate certain assumptions; furthermore, it is not known how accurately these different methods reproduce real transition events. Nevertheless, due to their computational efficiency in comparison to pure equilibrium MD, they remain important tools for generating transition ensembles and gaining intuition for the dynamics of macromolecular systems.…”

MORPH-PRO: A Novel Algorithm and Web Server for Protein Morphing

“…The structure which has the highest binding affinity for SP600125 is 1UKI which is the structure of JNK1 complexed with SP600125. The X-Ray structures docked with SP600125 rank significantly higher than the reconstructed P 1 and P 5 . This suggests that better side chain reconstruction could greatly improve the docking results.…”