Communication pathways bridge local and global conformations in an IgG4 antibody

Abstract The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recent evidence, however, points toward a nontrivial relation between the CDR and distal sites: variations in the bindin...

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Autores principales:	Thomas Tarenzi, Marta Rigoli, Raffaello Potestio
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66ff6bb769b24adb806d3721acdfc7ae
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spelling	oai:doaj.org-article:66ff6bb769b24adb806d3721acdfc7ae2021-12-05T12:12:14ZCommunication pathways bridge local and global conformations in an IgG4 antibody10.1038/s41598-021-02323-x2045-2322https://doaj.org/article/66ff6bb769b24adb806d3721acdfc7ae2021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02323-xhttps://doaj.org/toc/2045-2322Abstract The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recent evidence, however, points toward a nontrivial relation between the CDR and distal sites: variations in the binding strengths have been observed upon mutating residues separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies, whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR. These results support the hypothesis that pembrolizumab featues a multi-scale hierarchy of intertwined global and local conformational changes. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.Thomas TarenziMarta RigoliRaffaello PotestioNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas Tarenzi Marta Rigoli Raffaello Potestio Communication pathways bridge local and global conformations in an IgG4 antibody
description	Abstract The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recent evidence, however, points toward a nontrivial relation between the CDR and distal sites: variations in the binding strengths have been observed upon mutating residues separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies, whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR. These results support the hypothesis that pembrolizumab featues a multi-scale hierarchy of intertwined global and local conformational changes. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.
format	article
author	Thomas Tarenzi Marta Rigoli Raffaello Potestio
author_facet	Thomas Tarenzi Marta Rigoli Raffaello Potestio
author_sort	Thomas Tarenzi
title	Communication pathways bridge local and global conformations in an IgG4 antibody
title_short	Communication pathways bridge local and global conformations in an IgG4 antibody
title_full	Communication pathways bridge local and global conformations in an IgG4 antibody
title_fullStr	Communication pathways bridge local and global conformations in an IgG4 antibody
title_full_unstemmed	Communication pathways bridge local and global conformations in an IgG4 antibody
title_sort	communication pathways bridge local and global conformations in an igg4 antibody
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/66ff6bb769b24adb806d3721acdfc7ae
work_keys_str_mv	AT thomastarenzi communicationpathwaysbridgelocalandglobalconformationsinanigg4antibody AT martarigoli communicationpathwaysbridgelocalandglobalconformationsinanigg4antibody AT raffaellopotestio communicationpathwaysbridgelocalandglobalconformationsinanigg4antibody
_version_	1718372137119514624

Communication pathways bridge local and global conformations in an IgG4 antibody

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