10 research outputs found
Molecular dynamics simulations and drug discovery
This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role
Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region: Implications for Dimerization and Activation Mechanisms
The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites
Safety evaluation of the food enzyme alpha-amylase from a genetically modified Bacillus subtilis (strain NBA).
Safety evaluation of the food enzyme alpha-amylase from a genetically modified Bacillus subtilis (strain NBA).
Modelling and optimization studies on decolorization of brilliant green dye using integrated nanofiltration and photocatalysis
Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure
Cholesterol is an important regulator of membrane protein function. However, the exact
mechanisms involved in this process are still not fully understood. Here we study how the
tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds
cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of
TSPO by solid-state NMR spectroscopy reveals a dynamic monomer–dimer equilibrium of
TSPO in the membrane. Binding of cholesterol to TSPO’s cholesterol-recognition motif leads
to structural changes across the protein that shifts the dynamic equilibrium towards the
translocator monomer. Consistent with an allosteric mechanism, a mutation within the
oligomerization interface perturbs transmembrane regions located up to 35Ã… away from
the interface, reaching TSPO’s cholesterol-binding motif. The lower structural stability of the
intervening transmembrane regions provides a mechanistic basis for signal transmission. Our
study thus reveals an allosteric signal pathway that connects membrane protein tertiary and
quaternary structure with cholesterol binding.peerReviewe