Redistribution of flexibility in stabilizing antibody fragment mutants follows Le Châtelier's principle

Le Châtelier's principle is the cornerstone of our understanding of chemical equilibria. When a system at equilibrium undergoes a change in concentration or thermodynamic state (i.e., temperature, pressure, etc.), La Châtelier's principle states that an equilibrium shift will occur to offs...

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Bibliographic Details
Published in:PloS one 2014-03, Vol.9 (3), p.e92870-e92870
Main Authors: Li, Tong, Tracka, Malgorzata B, Uddin, Shahid, Casas-Finet, Jose, Jacobs, Donald J, Livesay, Dennis R
Format: Article
Language:English
Subjects:
Algorithms
Antigens - chemistry
Biochemistry
Bioinformatics
Biology and Life Sciences
Chemical bonds
Compensation
Computer applications
Constraint modelling
Databases, Protein
Enthalpy
Entropy
Equilibrium
Flexibility
Genomics
Hydrogen Bonding
Immunoglobulin Fragments - chemistry
Lymphotoxin
Lymphotoxin beta Receptor - chemistry
Models, Theoretical
Molecular Dynamics Simulation
Molecular structure
Mutant Proteins - chemistry
Mutants
Mutation
Mutation - genetics
Network topologies
Physical Sciences
Pliability
Protein Stability
Protein structure
Proteins
Quantitative Structure-Activity Relationship
Rigidity
Statistical analysis
Transition Temperature
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Summary:Le Châtelier's principle is the cornerstone of our understanding of chemical equilibria. When a system at equilibrium undergoes a change in concentration or thermodynamic state (i.e., temperature, pressure, etc.), La Châtelier's principle states that an equilibrium shift will occur to offset the perturbation and a new equilibrium is established. We demonstrate that the effects of stabilizing mutations on the rigidity ⇔ flexibility equilibrium within the native state ensemble manifest themselves through enthalpy-entropy compensation as the protein structure adjusts to restore the global balance between the two. Specifically, we characterize the effects of mutation to single chain fragments of the anti-lymphotoxin-β receptor antibody using a computational Distance Constraint Model. Statistically significant changes in the distribution of both rigidity and flexibility within the molecular structure is typically observed, where the local perturbations often lead to distal shifts in flexibility and rigidity profiles. Nevertheless, the net gain or loss in flexibility of individual mutants can be skewed. Despite all mutants being exclusively stabilizing in this dataset, increased flexibility is slightly more common than increased rigidity. Mechanistically the redistribution of flexibility is largely controlled by changes in the H-bond network. For example, a stabilizing mutation can induce an increase in rigidity locally due to the formation of new H-bonds, and simultaneously break H-bonds elsewhere leading to increased flexibility distant from the mutation site via Le Châtelier. Increased flexibility within the VH β4/β5 loop is a noteworthy illustration of this long-range effect.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0092870