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

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Jacobs, D. J., Li, T., & Livesay, D. R. (2014). Redistribution of flexibility in stabilizing antibody fragment mutants follows Le Chatelier's principle. Plos One.
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Faculty, Le Chatelier'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 Chatelier'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 double left right arrow 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-beta 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 Chatelier. Increased flexibility within the VH beta 4/beta 5 loop is a noteworthy illustration of this long-range effect.

Details
Title

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

Author(s)

Jacobs, Donald J.
Li, Tong
Livesay, Dennis R.

UNC Charlotte Affiliate Type

Faculty

Extent

1 online resource

Date Created

2014

Genre

articles

Resource Type

text

Abstract

Le Chatelier'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 Chatelier'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 double left right arrow 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-beta 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 Chatelier. Increased flexibility within the VH beta 4/beta 5 loop is a noteworthy illustration of this long-range effect.

Subjects--Topics

Immunoglobulins
Biology

Is Part Of

PLoS one

Language

English

Publisher's Version

doi:10.1371/journal.pone.0092870

Permalink

http://hdl.handle.net/20.500.13093/work:1008

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