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The role of metal ions in substrate recognition and stability of concanavalin A: a molecular dynamics study.

ABSTRACT: The binding of carbohydrate substrates to concanavalin A (Canavalia ensiformis agglutinin (ConA)) is essential for its interaction with various glycoproteins. Even though metal ions are known to control the sugar binding ability of legume lectins, the interplay between sugar and metal ion binding to ConA has not been elucidated in a detailed manner at the atomic level. We have carried out long, explicit solvent molecular dynamics simulations for tetrameric, dimeric, and monomeric forms of ConA in both the presence and absence of trimannoside and metal ions. Detailed analyses of these trajectories for various oligomeric forms under different environmental conditions have revealed dynamic conformational changes associated with the demetalization of ConA. We found that demetalization of ConA leads to large conformational changes in the ion binding loop, with some of the loop residues moving as far as 17 A with respect to their positions in the native trimannoside and metal ion-bound crystal structure. However, the ?-sheet core of the protein remains relatively unperturbed. In addition, the high mobility of the ion binding loop results in drifting of the substrates in the absence of bound metal ions. These simulations provide a theoretical rationale for previous experimental observations regarding the abolition of the sugar binding ability upon demetalization. We also found that the amino acid stretches of ConA, having high B-factor values in the crystal structure, show relatively greater mobility in the simulations. The overall agreement of the results of our simulations with various experimental studies suggests that the force field parameters and length of simulations used in our study are adequate to mimic the dynamic structural changes in the ConA protein.

SUBMITTER: Kaushik S

PROVIDER: S-EPMC2710015 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The role of metal ions in substrate recognition and stability of concanavalin A: a molecular dynamics study.

Kaushik Sandeep S Mohanty Debasisa D Surolia Avadhesha A

Biophysical journal 20090101 1

The binding of carbohydrate substrates to concanavalin A (Canavalia ensiformis agglutinin (ConA)) is essential for its interaction with various glycoproteins. Even though metal ions are known to control the sugar binding ability of legume lectins, the interplay between sugar and metal ion binding to ConA has not been elucidated in a detailed manner at the atomic level. We have carried out long, explicit solvent molecular dynamics simulations for tetrameric, dimeric, and monomeric forms of ConA i ...[more]

PMID: 18849415

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Project description:The small heat shock proteins (sHSPs) are a virtually ubiquitous and diverse group of molecular chaperones that can bind and protect unfolding proteins from irreversible aggregation. It has been suggested that intrinsic disorder of the N-terminal arm (NTA) of sHSPs is important for substrate recognition. To investigate conformations of the NTA that could recognize substrates we performed replica exchange molecular dynamics simulations. Behavior at normal and stress temperatures of the dimeric building blocks of dodecameric HSPs from wheat (Ta16.9) and pea (Ps18.1) were compared because they display high sequence similarity, but Ps18.1 is more efficient in binding specific substrates. In our simulations, the NTAs of the dimer are flexible and dynamic; however, rather than exhibiting highly extended conformations they retain considerable ?-helical character and contacts with the conserved ?-crystallin domain (ACD). Network analysis and clustering methods reveal that there are two major conformational forms designated either "open" or "closed" based on the relative position of the two NTAs and their hydrophobic solvent accessible surface area. The equilibrium constant for the closed to open transition is significantly different for Ta16.9 and Ps18.1, with the latter showing more open conformations at elevated temperature correlated with its more effective chaperone activity. In addition, the Ps18.1 NTAs have more hydrophobic solvent accessible surface than those of Ta16.9. NTA hydrophobic patches are comparable in size to the area buried in many protein-protein interactions, which would enable sHSPs to bind early unfolding intermediates. Reduced interactions of the Ps18.1 NTAs with each other and with the ACD contribute to the differences in dynamics and hydrophobic surface area of the two sHSPs. These data support a major role for the conformational equilibrium of the NTA in substrate binding and indicate features of the NTA that contribute to sHSP chaperone efficiency.

Dataset Information

The role of metal ions in substrate recognition and stability of concanavalin A: a molecular dynamics study.

Publications

The role of metal ions in substrate recognition and stability of concanavalin A: a molecular dynamics study.

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