Modeling Cu(II) Binding to Peptides Using the Extensible Systematic Force Field

Faina Ryvkin,Frederick T Greenaway

doi:10.1155/2010/724210

Abstract

The utility of the extensible systematic force field (ESFF) was tested for copper(II) binding to a 34-amino-acid Cu(II) peptide, which includes five histidine residues and is the putative copper-binding site of lysyl oxidase. To improve computational efficiency, distance geometry calculations were used to constrain all combinations of three histidine ligands to be within bonding distance of the copper and the best results were utilized as starting structures for the ESFF computations. All likely copper geometries were modeled, but the results showed only a small dependence on the geometrical model in that all resulted in a distorted square pyramidal geometry about the copper, some of the imidazole rings were poorly oriented for ligation to the Cu(II), and the copper-nitrogen bond distances were too long. The results suggest that ESFF should be used with caution for Cu(II) complexes where the copper-ligand bonds have significant covalency and when the ligands are not geometrically constrained to be planar.

Highlights

Molecular modeling of peptides and proteins interacting with transition-metal ions has the promise of elucidating a wide variety of biophysical phenomena
We recently modeled the copper-binding site of lysyl oxidase using a 34-residue peptide homologous to the putative copper-binding region of the enzyme [9] and we present the results of extensible systematic force field (ESFF) computations to model the structure of the copper peptide both to help clarify the structure of the peptide and to investigate the utility of ESFF for Cu(II) compounds where the ligands have few geometrical constraints such as those that are commonly found in bioinorganic complexes
The specific potentials for these geometries were applied for the metal ion according to the ESFF library list (Table 2), but no restrictions were made as to which amino acids could be the copper ligand; so the procedure was expected to explore the whole conformation space

Summary

Introduction

Molecular modeling of peptides and proteins interacting with transition-metal ions has the promise of elucidating a wide variety of biophysical phenomena. In the present work we have followed up on our spectroscopic study of a Cu(II)-binding LOXderived peptide containing these residues [9] with ESFF computations to better characterize the metal-binding region of LOX to help identify the copper ligands and to help assess the usefulness of ESFF in metallopeptide and metalloprotein structure predictions.

Results

Conclusion