A fully automatic evolutionary classification of protein folds: Dali Domain Dictionary version 3

218

261

The dynamics of proteins in aqueous solution has been investigated through a massive approach based on ''state of the art'' molecular dynamics simulations performed for all protein metafolds using the four most popular force fields (OPLS, CHARMM, AMBER, and GROMOS). A detailed analysis of the massive database of trajectories (>1.5 terabytes of data obtained using Ϸ50 years of CPU) allowed us to obtain a robust-consensus picture of protein dynamics in aqueous solution.force field ͉ molecular dynamics ͉ molecular modeling ͉ protein structure

Section: Methodsmentioning

confidence: 99%

A consensus view of protein dynamics

Rueda

Ferrer-Costa

Meyer

et al. 2007

218

261

“…The model was validated by calculating the solvation profile with SolvX software (38), which gave a satisfactory score of Ϫ17.5. The DALI algorithm (22) was used to align this model with the structure of the sensor domain of CitA (23).…”

Section: Methodsmentioning

confidence: 99%

Bacterial sensor kinase TodS interacts with agonistic and antagonistic signals

Büsch

Lacal

Martos

et al. 2007

105

The TodS/TodT two-component system controls expression of the toluene dioxygenase (TOD) pathway for the metabolism of toluene in Pseudomonas putida DOT-T1E. TodS is a sensor kinase that ultimately controls tod gene expression through its cognate response regulator, TodT. We used isothermal titration calorimetry to study the binding of different compounds to TodS and related these findings to their capacity to induce gene expression in vivo. Agonistic compounds bound to TodS and induced gene expression in vivo. Toluene was a powerful agonist, but ortho-substitutions of toluene reduced or abolished in vivo responses, although TodS recognized o-xylene with high affinity. These compounds were called antagonists. We show that agonists and antagonists compete for binding to TodS both in vitro and in vivo. The failure of antagonists to induce gene expression in vivo correlated with their inability to stimulate TodS autophosphorylation in vitro. We propose intramolecular TodS signal transmission, not molecular recognition of compounds by TodS, to be the phenomenon that determines whether a given compound will lead to activation of expression of the tod genes. Molecular modeling identified residues F46, I74, F79, and I114 as being potentially involved in the binding of effector molecules. Alanine substitution mutants of these residues reduced affinities (2-to 345-fold) for both agonistic and antagonistic compounds. Our data indicate that determining the inhibitory activity of antagonists is a potentially fruitful alternative to design specific two-component system inhibitors for the development of new drugs to inhibit processes regulated by two-component systems.histidine kinases ͉ isothermal titration calorimetry ͉ Pseudomonas ͉ two-component systems ͉ aromatic hydrocarbons

“…One such special case are the ''interlogs'' (i.e., pairs of interacting proteins that interact identically in two species) (19). It has already been demonstrated that the information about the interacting partners can be used to predict the fold (7,(20)(21)(22) or function (14,(23)(24)(25)(26)(27)) of a protein without considering its sequence. The usefulness of these approaches should grow with time, given the increasing amount of data about protein-protein interactions (20,24,28) (4).…”

Section: Detecting Remotely Related Proteins By Their Interactions Anmentioning

confidence: 99%

Detecting remotely related proteins by their interactions and sequence similarity

Espadaler

Aragüés²,

Eswar³

et al. 2005

The function of an uncharacterized protein is usually inferred either from its homology to, or its interactions with, characterized proteins. Here, we use both sequence similarity and protein interactions to identify relationships between remotely related protein sequences. We rely on the fact that homologous sequences share similar interactions, and, therefore, the set of interacting partners of the partners of a given protein is enriched by its homologs. The approach was benchmarked by assigning the fold and functional family to test sequences of known structure. Specifically, we relied on 1,434 proteins with known folds, as defined in the Structural Classification of Proteins (SCOP) database, and with known interacting partners, as defined in the Database of Interacting Proteins (DIP). For this subset, the specificity of fold assignment was increased from 54% for position-specific iterative blast to 75% for our approach, with a concomitant increase in sensitivity for a few percentage points. Similarly, the specificity of family assignment at the e-value threshold of 10-8 was increased from 70% to 87%. The proposed method would be a useful tool for large-scale automated discovery of remote relationships between protein sequences, given its unique reliance on sequence similarity and protein-protein interactions