PMID- 16049350
OWN - NLM
STAT- MEDLINE
DCOM- 20051027
LR  - 20050728
IS  - 1085-9195 (Print)
IS  - 1085-9195 (Linking)
VI  - 43
IP  - 2
DP  - 2005
TI  - Molecular dynamics simulation of a high-affinity antibody-protein complex: the 
      binding site is a mosaic of locally flexible and preorganized rigid regions.
PG  - 253-73
AB  - One nanosecond molecular dynamic (MD) simulation of anti-hen egg white lysozyme 
      (HEL) antibody HyHEL63 (HH63) complexed with HEL reveals rigid and flexible 
      regions of the HH63 binding site. Fifty conformations, extracted from the MD 
      trajectory at regular time intervals were superimposed on HH63-HEL X-ray crystal 
      structure, and the root mean squared deviations (RMSDs) and deviations in Calpha 
      atom positions between the X-ray structure and the MD conformer were measured. 
      Residue positions showing the large deviations in both light chain and heavy 
      chain of the antibody were same in all the MD conformers. The residue positions 
      showing smallest deviations were same for all the conformers in the case of light 
      chain, whereas relatively variable in the heavy chain. Positions of large and 
      small deviations fell in the complementarity determining regions (CDRs), for both 
      heavy and light chains. The larger deviations were in CDR-2 of light and CDR-1 of 
      heavy chain. Smaller deviations were in CDR-3 of light and CDR-2 and CDR-3 of 
      heavy chains. The large and small deviating regions highlight flexible and rigid 
      regions of HH63 binding site and suggest a mosaic binding mechanism, including 
      both "induced fit" and preconfigured "lock-and-key" type of binding. Combined 
      "induced fit" and "lock-and-key" binding would be a better definition for the 
      formation of large complexes, which bury larger surface area on binding, as in 
      the case of antibody-HEL complex. We further show that flexible regions, 
      comprising mostly charged and polar residues, form intermolecular interactions 
      with HEL, whereas rigid regions do not. Electrostatic complementarity between 
      HH63 and HEL also imply optimized binding affinity. Flexible and rigid regions of 
      a high-affinity antibody are selected during the affinity maturation of the 
      antibody and have specific functional significance. The functional importance of 
      local inherently flexible regions is to establish intermolecular contacts or they 
      play a key role in molecular recognition, whereas local rigid regions provide the 
      structural framework.
FAU - Sinha, Neeti
AU  - Sinha N
AD  - Johns Hopkins University, Baltimore, MD 21218, USA. nsinha1@jhu.edu
FAU - Smith-Gill, Sandra J
AU  - Smith-Gill SJ
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell Biochem Biophys
JT  - Cell biochemistry and biophysics
JID - 9701934
RN  - 0 (Antibodies)
RN  - 0 (Antigen-Antibody Complex)
RN  - EC 3.2.1.- (hen egg lysozyme)
RN  - EC 3.2.1.17 (Muramidase)
SB  - IM
MH  - Antibodies/*chemistry/immunology
MH  - Antigen-Antibody Complex/analysis/*chemistry/immunology
MH  - Computer Simulation
MH  - Elasticity
MH  - Models, Biological
MH  - *Models, Chemical
MH  - *Models, Molecular
MH  - Motion
MH  - Muramidase/analysis/*chemistry/immunology
MH  - Protein Binding
MH  - Protein Conformation
MH  - Structure-Activity Relationship
EDAT- 2005/07/29 09:00
MHDA- 2005/10/28 09:00
CRDT- 2005/07/29 09:00
PHST- 2005/07/29 09:00 [pubmed]
PHST- 2005/10/28 09:00 [medline]
PHST- 2005/07/29 09:00 [entrez]
AID - CBB:43:2:253 [pii]
AID - 10.1385/CBB:43:2:253 [doi]
PST - ppublish
SO  - Cell Biochem Biophys. 2005;43(2):253-73. doi: 10.1385/CBB:43:2:253.