RESUMO
Familial amyloidotic polyneuropathy (FAP) is strictly associated with point mutations of transthyretin (TTR) protein. The Tyr116-->Ser (Y116S) mutant TTR is an important amyloidogenic variant responsible for FAP. Structural dynamics of monomeric TR and its mutant (Y116S) may give some clue relating to amyloid formation. In this study, molecular dynamic simulation at 310 K has been performed on wild-type and mutant (Y116S) 'ITR monomer, which can provide the molecular insight of structural transition in the inner and outer strand of the protein. Results show that mutation in the H-strand (Tyr116-->Ser) leads to disruption of secondary structure and H-bonding pattern of some important parts of the inner DAGH-sheet of the protein. Especially, the residues T106, A108, L110 of G-strand, S117 and T119 of H-strand are affected, which are involved in the binding of thyroxin hormone. This unfolding of mutant structure during dynamics may cause instability in the protein and thus induce amyloidgenesis.
Assuntos
Mutação , Pré-Albumina/química , Pré-Albumina/genética , Amiloide/química , Biofísica/métodos , Simulação por Computador , Humanos , Ligação de Hidrogênio , Conformação Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Solventes/química , Termodinâmica , Tiroxina/química , Fatores de TempoRESUMO
The role of invariant water molecules in the activity of plant cysteine protease is ubiquitous in nature. On analysing the 11 different Protein DataBank (PDB) structures of plant thiol proteases, the two invariant water molecules W1 and W2 (W220 and W222 in the template 1PPN structure) were observed to form H-bonds with the O b atom of Asn 175. Extensive energy minimization and molecular dynamics simulation studies up to 2 ns on all the PDB and solvated structures clearly revealed the involvement of the H-bonding association of the two water molecules in fixing the orientation of the asparagine residue of the catalytic triad. From this study,it is suggested that H-bonding of the water molecule at the W1 invariant site better stabilizes the Asn residue at the active site of the catalytic triad.
Assuntos
Asparagina/química , Cisteína Endopeptidases/química , Proteínas de Plantas/química , Água/química , Catálise , Simulação por Computador , Cristalografia por Raios X , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Oxigênio/química , Plantas/enzimologia , Estrutura Terciária de ProteínaRESUMO
Transthyretin (TTR) is a protein whose aggregation and deposition causes amyloid diseases in human beings. Amyloid fibril formation is prevented by binding of thyroxin (T4) or its analogs to TTR. The MD simulation study of several solvated X-ray structures of apo and holo TTR has indicated the role of a conserved water molecule and its interaction with T4 binding residues Ser117 and Thr119. Geometrical and electronic consequences of those interactions have been exploited to design a series of thyroxin analogs (Mod1-4) by modifying 5' or 3' or both the iodine atoms of thyroxin. Binding energy of the designed ligands has been calculated by docking the molecules in tetrameric structure of the protein. Theoretically investigated pharmacological parameters along with the binding energy data indicate the potentiality of 3',5'-diacetyl-3,5-dichloro-l-thyronine (Mod4) to act as a better inhibitor for TTR-related amyloid diseases.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Pré-Albumina/química , Tiroxina/química , Humanos , Ligação de Hidrogênio , Ligantes , Pré-Albumina/metabolismo , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Serina/química , Treonina/química , Tiroxina/metabolismo , Água/químicaRESUMO
Cysteine protease is ubiquitous in nature. Excess activity of this enzyme causes intercellular proteolysis, muscle tissue degradation, etc. The role of water-mediated interactions in the stabilization of catalytically significant Asp158 and His159 was investigated by performing molecular dynamics simulation studies of 16 three-dimensional structures of plant thiol proteases. In the simulated structures, the hydrophilic W(1), W(2) and WD(1) centers form hydrogen bonds with the OD1 atom of Asp158 and the ND1 atom of His159. In the solvated structures, another water molecule, W(E), forms a hydrogen bond with the NE2 atom of His159. In the absence of the water molecule W(E), Trp177 (NE1) and Gln19 (NE2) directly interact with the NE2 atom of His159. All these hydrophilic centers (the locations of W(1), W(2), WD(1), and W(E)) are conserved, and they play a critical role in the stabilization of His-Asp complexes. In the water dynamics of solvated structures, the water molecules W(1) and W(2) form a water...water hydrogen-bonded network with a few other water molecules. A few dynamical conformations or transition states involving direct (His159 ND1...Asp158 OD1) and water-mediated (His159 ND1...W(2)...Asp158 OD1) hydrogen-bonded complexes are envisaged from these studies.