A modified PATH algorithm rapidly generates transition states comparable to those found by other well established algorithms

Abstract

PATH rapidly computes a path and a transition state between crystal structures by minimizing the Onsager-Machlup action. It requires input parameters whose range of values can generate different transition-state structures that cannot be uniquely compared with those generated by other methods. We outline modifications to estimate these input parameters to circumvent these difficulties and validate the PATH transition states by showing consistency between transition-states derived by different algorithms for unrelated protein systems. Although functional protein conformational change trajectories are to a degree stochastic, they nonetheless pass through a well-defined transition state whose detailed structural properties can rapidly be identified using PATH.

Combining multi-mutant and modular thermodynamic cycles to measure energetic coupling networks in enzyme catalysis

“…10(a) (Multimedia view)) 30,33,41 . Replica exchange discrete molecular dynamics 71 showed that the conformational transition state for TrpRS catalytic transition is narrowly defined structurally, and that it coincides with a saddle point in the respective conformational free energy landscape 41 (Fig. 10(b)).…”

“…Our recent demonstration that the equilibrium for this catalytic domain movement is driven only by the release of pyrophosphate 41 appears to be an additional mechanism ensuring that catalysis is coupled to (subsequent) domain movement, presumably regulated by tRNA binding. Using PPi release to change the overall conformational equilibrium resembles the behavior observed for myosin, for which the power stroke is initiated by orthophosphate release, whereas the release of adenosine-diphosphate happens only as the power stroke proceeds toward the rigor state 77–79 .…”

“…Computational studies relevant to inferences about the relevance of coupling energies 41 . (a) PATH trajectory [adapted from Weinreb et al , J. Biol.…”

Comparative Normal Mode Analysis of the Dynamics of DENV and ZIKV Capsids

“…We are interested in generating plausible paths between different conformations of the virus capsids, such as the “breathing" induced by increase of temperature (Fibriansah et al, 2013), and the changes observed during the maturation of the virus. We will develop new methods to find such plausible paths in very large systems such as viral capsids, where “plausible" refers to a path with minimal frustration, also defined as the Minimum Action Path (MAP) (Olender and Elber, 1996; Eastman et al, 2001; Franklin et al, 2007; Vanden-Eijnden and Heymann, 2008; Zhou et al, 2008; Chandrasekaran et al, 2016). Finally, we plan to study the impact of glycolsylation of the E protein and/or antibody binding on the virus capsids onto their dynamical properties.…”

Coding of Class I and II Aminoacyl-tRNA Synthetases

“…First, as neither intermediate construct would have sufficiently increased fitness to be selected, it suggests that the apparently separate evolutionary enhancements must have occurred coordinately, either because one of the two had already begun to function in trans , or because one or the other, or both modules could “grow” by smaller modular additions that did endow enhanced fitness [33]. Second, the modular thermodynamic cycle involving full-length TrpRS, the two distinct intermediates [33], and the Urzyme allowed measurement of a ΔΔG ‡ ~ − 5 kcal/mole coupling energy between the CP1 and anticodon-binding domains in the transition state of the amino acid activation reaction by full-length TrpRS [33], shedding new light on the general problem of intramolecular signaling or allostery [89–91]. …”