W. Wang et al., An analysis of the interactions between the Sem-5 SH3 domain and its ligands using molecular dynamics, free energy calculations, and sequence analysis, J AM CHEM S, 123(17), 2001, pp. 3986-3994
The Src-homology-3 (SH3) domain of the Caenorhabditis elegans protein Sem-5
binds proline-rich sequences. It is reported that the SH3 domains broadly
accept amide: N-substituted residues instead of only recognizing prolines o
n the basis of side chain shape or rigidity. We have studied the interactio
ns between Sem-5 and its ligands using molecular dynamics (MD), free energy
calculations, and sequence analysis. Relative binding free energies, estim
ated by a method called MM/PBSA, between different substitutions at sites -
1, 0, and +2 of the peptide are consistent with the experimental data. A n
ew method to calculate atomic partial charges. AM1-BCC method, is also used
in the binding foe energy calculations for different N-substitutions at si
te -1. The results are very similar to those obtained from widely used RESP
charges in the AMBER force field. AM1-BCC charges can be calculated more r
apidly for any organic molecule than can the RESP charges. Therefore, their
use can enable a broader and more efficient application of the MM/PBSA met
hod in drug design. Examination of each component of the free energy leads
to the construction of van der Weals interaction energy profiles for each l
igand as well as for wild-type and mutant Sem-5 proteins. The profiles and
free energy calculations indicate that the van der Waals interactions betwe
en the ligands and the receptor determine whether an N- or a C alpha -subst
ituted residue is favored at each site. A VC value (defined as a product of
the conservation percentage of each residue and its van der WaaIs interact
ion energy with the ligand) is used to identify several residues on the rec
eptor that are critical for specificity and binding affinity. This VC value
may have a potential use in identifying crucial residues for any Ligand-pr
otein or protein-protein system. h Mutations at two of those crucial residu
es, N190 and N206, are examined. One mutation, N190I, is predicted to reduc
e the selectivity of the N-substituted residue at site -1 of the ligand and
is shown to bind similarly with N- and C alpha -substituted residues at th
at site.