Linked Life Data

9542997

Source:http://linkedlifedata.com/resource/pubmed/id/9542997

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1998-5-15
pubmed:abstractText
Dissecting ligand-protein binding free energies in individual contributions of protein residues (which are referred to here as 'group contributions') is of significant importance. For example, such contributions could help in estimating the corresponding mutational effects and in studies of drug resistance problems. However, the meaning of group contributions is not always uniquely defined and the approximations for rapid estimates of such contributions are not well developed. In this paper, the nature of group contributions to binding free energy is examined, focusing particularly on electrostatic contributions which are expected to be well behaved. This analysis examines different definitions of group contributions; the 'relaxed' group contributions that represent the change in binding energy upon mutation of the given residue to glycine, and the 'non-relaxed' group contributions that represent the scaled Coulomb interaction between the given residue and the ligand. Both contributions are defined and evaluated by the linear response approximation (LRA) of the PDLD/ S method. The present analysis considers the binding of pepstatin to endothiapepsin and 23 of its mutants as a test case for a neutral ligand. The 'non-relaxed' group contributions of 15 endothiapepsin residues show significant peaks in the 'electrostatic fingerprint'. The residues that contribute to the electrostatic fingerprint are located in the binding site of endothiapepsin. They include the aspartic dyad (Asp32, Asp215) with adjacent residues and the flap region. Twelve of these 15 residues have a heavy atom distance of <3.75 A to pepstatin. The contributions of 8 (10) of these 12 residues can be reconciled with the calculated 'relaxed' group contributions where one allows the protein and solvent (solvent only) to relax upon mutation of the given residue to glycine. On the other hand, it was found that residues at the second 'solvation shell' can have relaxed contributions that are not captured by the non-relaxed approach. Hence, whereas residues with significant non-relaxed electrostatic contributions are likely to contribute to binding, residues with small non-relaxed contributions may still affect the binding energy. At any rate, it is established here that even in the case of uncharged inhibitors it is possible to use the non-relaxed electrostatic fingerprint to detect 'hot' residues that are responsible for binding. This is significant since some versions of the non-relaxed approximation are faster by several orders of magnitude than more rigorous approaches. The general applicability of this approach is outlined, emphasizing its potential in studies of drug resistance where it is crucial to have a rapid way of anticipating the effect of mutation on both drug binding and catalysis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0269-2139
pubmed:author
pubmed:issnType
Print
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1363-72
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
A fast estimate of electrostatic group contributions to the free energy of protein-inhibitor binding.
pubmed:affiliation
Department of Chemistry, University of Southern California, Los Angeles 90089-1062, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't