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New general approach for determining the solution structure of a ligand bound weakly to a receptor: structure of a fibrinogen Aα‐like peptide bound to thrombin(S195A) obtained using NOE distance constraints and an ECEPP/3 flexible docking program
Author(s) -
Maurer Muriel C.,
Trosset JeanYves,
Lester Cathy C.,
DiBella Elsie E.,
Scheraga Harold A.
Publication year - 1999
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19990101)34:1<29::aid-prot4>3.0.co;2-u
Subject(s) - searching the conformational space for docking , docking (animal) , ligand (biochemistry) , chemistry , peptide , stereochemistry , protein structure , crystallography , receptor , biochemistry , medicine , nursing
A new approach incorporating flexible docking simulations and NMR data is presented for calculating the bound conformation of a ligand that interacts weakly with an enzyme. This approach consists of sampling directly the conformation of a flexible ligand inside a receptor active site containing surrounding flexible loops. To make this sampling efficient, a ligand‐growing procedure has been adopted. Optimization of the ECEPP/3‐plus‐NOE constraint function is carried out by using a collective variable Monte Carlo minimization technique. Numerous energy minimizations are made possible for such a large system by using a Bezier splines energy grid technique. This new flexible docking approach was applied to determine the structure of a fibrinogen Aα‐like peptide ( 7 DFLAEGGGVRGPRV 20 ) bound to an active site mutant of thrombin [thrombin(S195A)]. Structure calculations of the bound ligand, using 2D‐transferred NOESY distance constraints in the DIANA program, showed that the N‐terminal portion of the peptide (D7‐R16) involves a chain reversal, whereas the C‐terminal portion (G17‐V20) adopts a fold that exists in several different orientations. In addition, the ECEPP/3 flexible docking package was used to assess the conformational variability of the ligand and surrounding 60D‐insertion loop of thrombin. Amino acid residues (17–20) of the peptide interact with a region of the enzyme that exhibits broad specificity, with a preferred direction between the 60D‐insertion loop and Pro37 of thrombin. Proteins 1999;34:29–48. © 1999 Wiley‐Liss, Inc.