Mutations in Antibody Fragments Modulate Allosteric Response Via Hydrogen-Bond Network Fluctuations

Srivastava, Amit; Tracka, Malgorzata B.; Uddin, Shahid; Casas‐Finet, José R.; Livesay, Dennis R.; Jacobs, Donald J.

doi:10.1016/j.bpj.2016.03.033

Cited by 13 publications

(17 citation statements)

References 60 publications

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“…This finding demonstrates the complex nature of allostery and might indicate that the conservation of allosteric mechanism exists only across short evolutionary distances. In a second study, the MPM was applied to identify putative allosteric sites in a set of six single chain‐Fv fragments of the anti‐lymphotoxin‐β receptor antibody . The findings from this study on monoclonal antibodies indicate that the allosteric response is sensitive to mutations through changes in the hydrogen bonding network, and results from rigidity analysis support what is found in practice when redesigning monoclonal antibodies either for function and/or thermodynamic stability.…”

Section: Applicationssupporting

confidence: 54%

Rigidity theory for biomolecules: concepts, software, and applications

Hermans

Pfleger

Nutschel

et al. 2017

WIREs Comput Mol Sci

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The mechanical heterogeneity of biomolecular structures is intimately linked to their diverse biological functions. Applying rigidity theory to biomolecules identifies this heterogeneous composition of flexible and rigid regions, which can aid in the understanding of biomolecular stability and long-ranged information transfer through biomolecules, and yield valuable information for rational drug design and protein engineering. We review fundamental concepts in rigidity theory, ways to represent biomolecules as constraint networks, and methodological and algorithmic developments for analyzing such networks and linking the results to biomolecular function. Software packages for performing rigidity analyses on biomolecules in an efficient, automated way are described, as are rigidity analyses on biomolecules including the ribosome, viruses, or transmembrane proteins. The analyses address questions of allosteric mechanisms, mutation effects on (thermo-)stability, protein (un-)folding, and coarse-graining of biomolecules. We advocate that the application of rigidity theory to biomolecules has matured in such a way that it could be broadly applied as a computational biophysical method to scrutinize biomolecular function from a structure-based point of view and to complement approaches focused on biomolecular dynamics. We discuss possibilities to improve constraint network representations and to perform large-scale and prospective studies.

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Section: Applicationssupporting

confidence: 54%

Rigidity theory for biomolecules: concepts, software, and applications

Hermans

Pfleger

Nutschel

et al. 2017

WIREs Comput Mol Sci

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“…To regulate the immune response, antibody‐antigen interaction should send a signal to allosteric sites for complement activation and Fc receptors binding. Signal transduction pathways could depend on sequences of the variable regions and allotypes, possibly through hydrogen bonding network, electrostatic interactions, resulting from population shift of dynamic conformations . The CH1 region affects antigen and other constant regions, most likely through interactions with its neighboring CL domain as well as by transmitting structural and dynamics perturbations to the Ig hinge region and back to the VH domain .…”

Section: Discussionmentioning

confidence: 80%

Local and global anatomy of antibody‐protein antigen recognition

Wang

Zhu

et al. 2017

J of Molecular Recognition

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Deciphering antibody-protein antigen recognition is of fundamental and practical significance. We constructed an antibody structural dataset, partitioned it into human and murine subgroups, and compared it with nonantibody protein-protein complexes. We investigated the physicochemical properties of regions on and away from the antibody-antigen interfaces, including net charge, overall antibody charge distributions, and their potential role in antigen interaction. We observed that amino acid preference in antibody-protein antigen recognition is entropy driven, with residues having low side-chain entropy appearing to compensate for the high backbone entropy in interaction with protein antigens. Antibodies prefer charged and polar antigen residues and bridging water molecules. They also prefer positive net charge, presumably to promote interaction with negatively charged protein antigens, which are common in proteomes. Antibody-antigen interfaces have large percentages of Tyr, Ser, and Asp, but little Lys. Electrostatic and hydrophobic interactions in the Ag binding sites might be coupled with Fab domains through organized charge and residue distributions away from the binding interfaces. Here we describe some features of antibody-antigen interfaces and of Fab domains as compared with nonantibody protein-protein interactions. The distributions of interface residues in human and murine antibodies do not differ significantly. Overall, our results provide not only a local but also a global anatomy of antibody structures.

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“…Through their changes, they result in population shift of dynamic conformations. 48 However, intramolecular signaling is complex and exactly how it takes place in distinct structures and under certain conditions is still not entirely clear. 14,32,33 The Fab variable domain recognizes the antigen, followed by effector activation by the Fc domain.…”

Section: Discussionmentioning

confidence: 99%

Antigen binding allosterically promotes Fc receptor recognition

Zhao

Nussinov

2018

mAbs

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A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain. We simulated four antibody complexes: free antibody, antigen-bound antibody, FcR-bound antibody, and an antigen-antibody-FcR complex. We found that, in the antibody's "T/Y" conformation, the glycans, and the Fc domain all respond to antigen binding, with the antibody population shifting to two dominant clusters, both with the Fc-receptor binding site open. The simulations reveal that the Fc-glycan-receptor complexes also segregate into two conformational clusters, one corresponding to the antigen-free antibody-FcR baseline binding, and the other with an antigen-enhanced antibody-FcR interaction. Our study confirmed allosteric communications in antibody-antigen recognition and following FcR activation. Even though we observed allosteric communications through the IgG domains, the most important mechanism that we observed is the communication via population shift, stimulated by antigen binding and propagating to influence FcR recognition.

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Mutations in Antibody Fragments Modulate Allosteric Response Via Hydrogen-Bond Network Fluctuations

Cited by 13 publications

References 60 publications

Rigidity theory for biomolecules: concepts, software, and applications

Rigidity theory for biomolecules: concepts, software, and applications

Local and global anatomy of antibody‐protein antigen recognition

Antigen binding allosterically promotes Fc receptor recognition

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