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Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin

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Title Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin
 
Creator CHAKRABORTI, S
CHAKRAVARTY, D
GUPTA, S
CHATTERJI, BP
DHAR, G
PODDAR, A
PANDA, D
CHAKRABARTI, P
DASTIDAR, SG
BHATTACHARYYA, B
 
Subject COMBRETASTATIN A4 PHOSPHATE
MOLECULAR-DYNAMICS
COLCHICINE-BINDING
B-RING
C-7 SUBSTITUENT
IN-VITRO
PHASE-I
DRUG
THERMODYNAMICS
ASSOCIATION
 
Description Tubulin, an alpha,beta heterodimer, has four distinct ligand binding sites (for paclitaxel, peloruside/laulimalide, via, and colchicine). The site where colchicine binds is a promising drug target for arresting cell division and has been observed to accommodate compounds that are structurally diverse but possess comparable affinity. This investigation, using two such structurally different ligands as probes (one being colchicine itself and another, TN16), aims to provide insight into the origin of this diverse acceptability to provide a better perspective for the design of novel therapeutic molecules. Thermodynamic measurements reveal interesting interplay between entropy and enthalpy. Although both these parameters are favourable for TN16 binding (Delta H < 0, Delta S > 0), but the magnitude of entropy has the determining role for colchicine binding as its enthalpic component is destabilizing (Delta H > 0, Delta S > 0). Molecular dynamics simulation provides atomistic insight into the mechanism, pointing to the inherent flexibility of the binding pocket that can drastically change its shape depending on the ligand that it accepts. Simulation shows that in the complexed states both the ligands have freedom to move within the binding pocket; colchicine can switch its interactions like a "flying trapeze", whereas TN16 rocks like a "swing cradle", both benefiting entropically, although in two different ways. Additionally, the experimental results with respect to the role of solvation entropy correlate well with the computed difference in the hydration: water molecules associated with the ligands are released upon complexation. The complementary role of van der Waals packing versus flexibility controls the entropy-enthalpy modulations. This analysis provides lessons for the design of new ligands that should balance between the "better fit" and "flexibility", instead of focusing only on the receptor-ligand interactions.
 
Publisher AMER CHEMICAL SOC
 
Date 2014-10-17T04:17:23Z
2014-10-17T04:17:23Z
2012
 
Type Article
 
Identifier BIOCHEMISTRY, 51(36)7138-7148
0006-2960
1943-295X
http://dx.doi.org/10.1021/bi300474q
http://dspace.library.iitb.ac.in/jspui/handle/100/15927
 
Language en