Primary tabs

Decomposing dynamical couplings in mutated scFv antibody fragments into stabilizing and destabilizing effects

Search for this publication on Google Scholar
Jacobs, D. J., Ramaprasad, A. S. E., Uddin, S., & Casas-Finet, J. (2017). Decomposing dynamical couplings in mutated scFv antibody fragments into stabilizing and destabilizing effects. Journal Of The American Chemical Society. https://doi.org/doi:10.1021/jacs.7b09268
Download PDF

Analytics

1969 views ◎
56 downloads ⇓


Description

Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies.

Details
Title

Decomposing dynamical couplings in mutated scFv antibody fragments into stabilizing and destabilizing effects

Author(s)

Jacobs, Donald J.
Ramaprasad, Azhagiya Singam Ettayapuram
Uddin, Shahid
Casas-Finet, Jose

UNC Charlotte Affiliate Type

Faculty

Publisher

American Chemical Society

Extent

1 online resource

Date Published

2017-11-15

Material Type

Journal article

Genre

articles

Resource Type

text

Abstract

Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies.

Subjects--Topics

Amino acid sequence
Immunoglobulins

Is Part Of

Journal of the American Chemical Society

Volume

139

Issue

48

ISSN

0002-7863

Beginning Page Number

17508

Ending Page Number

17517

Language

English

Published Version (Please cite this version)

doi:10.1021/jacs.7b09268

Publisher's Version

https://pubs.acs.org/doi/10.1021/jacs.7b09268

Permalink

http://hdl.handle.net/20.500.13093/work:59

Rights

This item may be protected by copyright and other related rights. Atkins Library provides access to this item for educational and research purposes only; other uses require the permission of the copyright holder.