PMID- 20196074
OWN - NLM
STAT- MEDLINE
DCOM- 20100823
LR  - 20211020
IS  - 1469-896X (Electronic)
IS  - 0961-8368 (Print)
IS  - 0961-8368 (Linking)
VI  - 19
IP  - 5
DP  - 2010 May
TI  - A flexible docking scheme to explore the binding selectivity of PDZ domains.
PG  - 914-28
LID - 10.1002/pro.366 [doi]
AB  - Modeling of protein binding site flexibility in molecular docking is still a 
      challenging problem due to the large conformational space that needs sampling. 
      Here, we propose a flexible receptor docking scheme: A dihedral restrained 
      replica exchange molecular dynamics (REMD), where we incorporate the normal modes 
      obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up 
      the search towards correct binding site conformations. To our knowledge, this is 
      the first approach that uses ENM modes to bias REMD simulations towards binding 
      induced fluctuations in docking studies. In our docking scheme, we first obtain 
      the deformed structures of the unbound protein as initial conformations by moving 
      along the binding fluctuation mode, and perform REMD using the ENM modes as 
      dihedral restraints. Then, we generate an ensemble of multiple receptor 
      conformations (MRCs) by clustering the lowest replica trajectory. Using 
      ROSETTALIGAND, we dock ligands to the clustered conformations to predict the 
      binding pose and affinity. We apply this method to postsynaptic 
      density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding 
      specificity. Our approach produces the lowest energy bound complexes with an 
      average ligand root mean square deviation of 0.36 A. We further test our method 
      on (i) homologs and (ii) mutant structures of PDZ where mutations alter the 
      binding selectivity. In both cases, our approach succeeds to predict the correct 
      pose and the affinity of binding peptides. Overall, with this approach, we 
      generate an ensemble of MRCs that leads to predict the binding poses and 
      specificities of a protein complex accurately.
FAU - Gerek, Z Nevin
AU  - Gerek ZN
AD  - Center for Biological Physics, Arizona State University, Tempe, Arizona, USA.
FAU - Ozkan, S Banu
AU  - Ozkan SB
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Protein Sci
JT  - Protein science : a publication of the Protein Society
JID - 9211750
RN  - 0 (Proteins)
SB  - IM
MH  - Binding Sites
MH  - Cluster Analysis
MH  - *Molecular Dynamics Simulation
MH  - Mutation
MH  - *PDZ Domains
MH  - Protein Binding
MH  - Protein Conformation
MH  - Proteins/*chemistry/metabolism
PMC - PMC2868235
EDAT- 2010/03/03 06:00
MHDA- 2010/08/24 06:00
PMCR- 2011/05/01
CRDT- 2010/03/03 06:00
PHST- 2010/03/03 06:00 [entrez]
PHST- 2010/03/03 06:00 [pubmed]
PHST- 2010/08/24 06:00 [medline]
PHST- 2011/05/01 00:00 [pmc-release]
AID - 10.1002/pro.366 [doi]
PST - ppublish
SO  - Protein Sci. 2010 May;19(5):914-28. doi: 10.1002/pro.366.