Calorimetric Studies of Metal Binding to Tetracycline. Role of Solvent Structure in Defining the Selectivity of Metal Ion-Drug Interactions

1995 ◽  
Vol 34 (11) ◽  
pp. 3083-3086 ◽  
Author(s):  
T. Ohyama ◽  
J. A. Cowan
Keyword(s):  
Drug Interactions ◽  
Metal Binding ◽  
Metal Ion ◽  
Solvent Structure ◽  
Calorimetric Studies ◽  
Role Of Solvent

Role of solvent structure in solution theory

1977 ◽  
Vol 73 (5) ◽  
pp. 630-648 ◽  
Author(s):  
Stjepan Marčelja ◽  
D. John Mitchell ◽  
Barry W. Ninham ◽  
Michael J. Sculley
Keyword(s):  
Solvent Structure ◽  
Solution Theory ◽  
Structure In Solution ◽  
Role Of Solvent

scholarly journals Hybrid QM/MM Simulations Confirm Zn(II) Coordination Sphere That Includes Four Cysteines from the P2 × 4R Head Domain

2021 ◽  
Vol 22 (14) ◽  
pp. 7288
Author(s):  
Francisco Andrés Peralta ◽  
J. Pablo Huidobro-Toro ◽  
Raúl Mera-Adasme
Keyword(s):  
Binding Site ◽  
Coordination Sphere ◽  
Metal Binding ◽  
Metal Ion ◽  
Dynamic Simulations ◽  
Metal Binding Site ◽  
Head Domain ◽  
Water Ligands ◽  
Role Of Zn

To ascertain the role of Zn(II) as an allosteric modulator on P2X4R, QM/MM molecular dynamic simulations were performed on the WT and two P2X4R mutants suggested by previous electrophysiological data to affect Zn(II) binding. The Gibbs free energy for the reduction of the putative P2X4R Zn(II) binding site by glutathione was estimated at −22 kcal/mol. Simulations of the WT P2X4R head domain revealed a flexible coordination sphere dominated by an octahedral geometry encompassing C126, N127, C132, C149, C159 and a water molecule. The C132A mutation disrupted the metal binding site, leading to a coordination sphere with a majority of water ligands, and a displacement of the metal ion towards the solvent. The C132A/C159A mutant exhibited a tendency towards WT-like stability by incorporating the R148 backbone to the coordination sphere. Thus, the computational findings agree with previous experimental data showing Zn(II) modulation for the WT and C132A/C159A variants, but not for the C132A mutant. The results provide molecular insights into the nature of the Zn(II) modulation in P2X4R, and the effect of the C132A and C132A/C159A mutations, accounting for an elusive modulation mechanism possibly occurring in other extracellular or membrane protein.

Equilibrium and Non-Equilibrium Molecular Dynamics Simulations Provide Potential Mechanisms for the Loss of Ligand Binding to αIIbβ3 Mutants Affecting the Ligand-Induced Metal Binding Site (LIMBS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1805-1805
Author(s):  
Marta Murcia ◽  
Marketa Jirouskova ◽  
Jihong Li ◽  
Barry S. Coller ◽  
Filizola Marta
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Cyclic Peptide ◽  
Hek293 Cells ◽  
Peptide Ligand ◽  
Non Equilibrium

Abstract Although the role of the β3 MIDAS metal ion in ligand binding to αIIbβ3 is well established, serving as the site of interaction of the ligand Asp residue, the role of the nearby LIMBS metal ion is less well defined. Previous studies suggested a role for the LIMBS in ligand binding. We confirmed this by showing that HEK293 cells expressing normal αIIbβ3 adhered to both immobilized fibrinogen and the RGD-containing venom echistatin in the presence of either Mg++/Ca++ or Mn++, whereas two different αIIbβ3 LIMBS mutants (β3 N215A and D217A) failed to adhere to either protein. In addition, we found that both mutations also increased the binding of mAb AP5, which recognizes a ligand-induced binding site (LIBS) in the β3 PSI domain (normal 7±4% vs N215A 46±12% and D217A 41±20% of mAb anti-αIIb (HIP8) binding; mean±SD, n=6, p<0.05 for both), indicating that the mutations caused allosteric changes in the conformation of the receptor. To define the mechanism(s) by which the LIMBS mutants affect ligand binding, we carried out equilibrium and non-equilibrium (steered) molecular dynamics (MD) simulations of the cyclic peptide ligand eptifibatide in complex with either the fully hydrated normal αIIbβ3 integrin headpiece (PDB 1TY6) or the equivalent β3 D217A mutant, with and without the LIMBS metal ion. Simulations were carried out using the GROMACS package with the OPLS all-atom force-field. During the simulation, the hybrid domain of the D217A mutant demonstrated greater structural fluctuations than the normal αIIbβ3. Although Craig et al. have reported the appearance of a new contact between the RGD peptide ligand Asp carboxyl and the LIMBS metal ion in αVβ3 after 10 ps of a 1 ns simulation, we did not observe the appearance of such an interaction between the eptifibatide carboxyl and the normal αIIbβ3 LIMBS metal ion even after 20 ns. We did, however, observe such an interaction with the LIMBS metal ion in the D217A mutant. This interaction was facilitated by the movement of the LIMBS ~ 2 Å closer to the MIDAS, and was accompanied by rearrangements of the LIMBS coordinating residues D158 and N215. When the D217A mutant simulation was performed in the absence of the LIMBS metal ion, changes in the orientation of E220 were also observed. The D217A mutant demonstrated increased fluctuations in the C177–C184 specificity-determining loop (SDL), which has been implicated in ligand binding, and decreased fluctuations in K209. Steered MD were used to investigate the pulling forces required to unbind eptifibatide from its binding site. Notably, although the unbinding force decreased modestly when the LIMBS metal ion was removed, it required removal of both the LIMBS and MIDAS metal ions to effect a marked reduction in unbinding force. The binding free energies of the association of the αIIb and β3 subunits were also calculated, and the D217A mutant in the presence of the LIMBS metal ion demonstrated much tighter binding than normal integrin αIIbβ3 (ΔGb −162±6 vs −119±6 Kcal/mol; mean±SD; n=500). We conclude that the LIMBS plays a crucial role in ligand binding to αIIbβ3, perhaps by virtue of its effects on the coordination of the MIDAS, the accentuated mobility of specific domains (e.g., the SDL and the hybrid domains), and/or the number and strength of contacts between αIIb and β3.

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