Molecular Dynamics Simulations of Bromodomains Reveal Binding-Site Flexibility and Multiple Binding Modes of the Natural Ligand Acetyl-Lysine

Experimental protein structures provide spatial information at the atomic level. A further dimension, time, is supplemented by molecular dynamics. Since the pioneering work on the 58‐residue inhibitor of bovine pancreatic trypsin in the group of Martin Karplus in the seventies, molecular dynamics si...

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Bibliographic Details
Published in:Israel journal of chemistry 2014-08, Vol.54 (8-9), p.1084-1092
Main Authors: Spiliotopoulos, Dimitrios, Caflisch, Amedeo
Format: Article
Language:English
Subjects:
atomistic simulations
Binding
Binding sites
computational chemistry
drug design
epigenetics
Flexibility
Histones
Inhibitors
Molecular dynamics
Proteins
proteinprotein interactions
Recognition
Simulation
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Summary:Experimental protein structures provide spatial information at the atomic level. A further dimension, time, is supplemented by molecular dynamics. Since the pioneering work on the 58‐residue inhibitor of bovine pancreatic trypsin in the group of Martin Karplus in the seventies, molecular dynamics simulations have shown that the intrinsic flexibility of proteins is essential for their function. Here, we review simulation studies of bromodomains. These protein modules are involved in the recognition of acetylated lysine side chains, a post‐translational modification frequently observed in histone tails. The molecular dynamics simulations have unmasked: (i) the large plasticity of the loops lining the acetyl‐lysine binding site (coupled to its self‐occlusion), and (ii) multiple binding modes of acetyl‐lysine. These simulation results suggest that recognition of histone tails by bromodomains is modulated by their intrinsic flexibility, and further corroborate the utility of molecular dynamics in understanding (macro)molecular recognition.
ISSN:0021-2148
1869-5868
DOI:10.1002/ijch.201400009