Antigen binding by conformational selection in near-germline antibodies

Blackler, R.J.; Müller‐Loennies, Sven; Pokorny-Lehrer, Barbara; Legg, Max S G; Brade, Lore; Brade, Helmut; Kosma, Paul; Evans, Stephen V.

doi:10.1016/j.jbc.2022.101901

Cited by 5 publications

(7 citation statements)

References 65 publications

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“…The changes in the pattern of promiscuity of the RBD can be well explained by physicochemical modification in its amino acid sequence. Thus, experiments with antibodies have demonstrated that structural dynamics of the antigen‐binding site is one of the main factors determining the reactivity to unrelated antigens that is, antibody polyreactivity 57–62 . The structural dynamics of the RBD deduced by the signature of the activation thermodynamics can explain the tendency of the RBD‐Wuhan for promiscuous interactions with unrelated to ACE2 proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, experiments with antibodies have demonstrated that structural dynamics of the antigen‐binding site is one of the main factors determining the reactivity to unrelated antigens that is, antibody polyreactivity. 57 , 58 , 59 , 60 , 61 , 62 The structural dynamics of the RBD deduced by the signature of the activation thermodynamics can explain the tendency of the RBD‐Wuhan for promiscuous interactions with unrelated to ACE2 proteins. A flexible binding site can accommodate through induced‐fit to distinct molecular motifs.…”

Section: Discussionmentioning

confidence: 99%

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Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS‐CoV‐2

et al. 2022

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SARS‐CoV‐2 infects cells by attachment to its receptor—the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS‐CoV‐2 variants of concern (VOC). Data on kinetics, activation‐, and equilibrium thermodynamics of binding of the receptor binding domain (RBD) from VOC with ACE2 as well as data from computational protein electrostatics revealed a profound remodeling of the physicochemical characteristics of the interaction during the evolution. Thus, as compared to RBDs from Wuhan strain and other VOC, Omicron RBD presented as a unique protein in terms of conformational dynamics and types of non‐covalent forces driving the complex formation with ACE2. Viral evolution resulted in a restriction of the RBD structural dynamics, and a shift to a major role of polar forces for ACE2 binding. Further, we investigated how the reshaping of the physicochemical characteristics of interaction affects the binding specificity of S proteins. Data from various binding assays revealed that SARS‐CoV‐2 Wuhan and Omicron RBDs manifest capacity for promiscuous recognition of unrelated human proteins, but they harbor distinct reactivity patterns. These findings might contribute for mechanistic understanding of the viral tropism and capacity to evade immune responses during evolution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS‐CoV‐2

et al. 2022

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“…Thus, experiments with antibodies have demonstrated that structural dynamics of the antigenbinding site is one of the main factors determining the reactivity to unrelated antigens i.e. antibody polyreactivity [57][58][59][60][61][62] . The structural dynamics of the RBD deduced by the signature of the activation thermodynamics can explain the tendency of the RBD-Wuhan for promiscuous interactions with unrelated to ACE2 proteins.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2

Planchais

Reyes-Ruiz

Lacombe

et al. 2022

Preprint

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SARS-CoV-2 infects cells by attachment to its receptor – the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS-CoV-2 variants of concern (VOC). Data on kinetics, activation- and equilibrium thermodynamics of binding of the receptor binding domain (RBD) from VOC with ACE2 as well as data from computational protein electrostatics revealed a profound remodeling of the physicochemical characteristics of the interaction during the evolution. Thus, as compared to RBDs from Wuhan strain and other VOC, Omicron RBD presented as a unique protein in terms of conformational dynamics and types of non-covalent forces driving the complex formation with ACE2. Viral evolution resulted in a restriction of the RBD structural dynamics, and a shift to a major role of electrostatic forces for ACE2 binding. Further, we investigated how the reshaping of the physicochemical qualities affect the functional properties of S proteins. Data from various binding assays revealed that SARS-CoV-2 Wuhan and Omicron RBDs manifest capacity for off-target (promiscuous) recognition of multiple unrelated proteins, but they harbor distinct reactivity patterns. This study provides mechanistic explanations for changes in the viral tropism, infectivity, and capacity to evade immune responses during evolution.SignificanceSince the beginning of COVID-19 pandemic SARS-CoV-2 has constantly mutated. Certain variants of the virus have manifested increased infectivity. The mutations often localized in the receptor binding domain (RBD). However, a little is known about the consequences of these mutations on mechanism of receptor binding. By using interdisciplinary approach, we depicted the evolution trajectory of the interactions of RBD with its receptor and with off-targets (unrelated proteins). The viral evolution resulted in a reduction of the structural dynamics of RBD and a shift to a major role of charge interactions for receptor binding. Strikingly, RBD Omicron manifested qualities of a completely different protein as compared to other viral variants in term of its receptor binding and repertoire of recognized off-target molecules.

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“…Molecular dynamic simulations provided an additional conformational landscape which indicated how the incoming pathogen led to further CDR conformational divergence while maintaining a similar overall backbone topology [ 25 ]. The analysis of multiple liganded and unliganded crystal structures of the near-germline anticarbohydrate antibodies S25–2 and S25–39 confirmed conformational flexibility [ 26 ] in antibody-antigen recognition, enabling their limited germline repertoire to match the overwhelming diversity of potential antigens [ 27 ]. Conformational selection has been proposed to be a common ligand–receptor interaction mechanism in addition to lock-and-key and induced fit [ 26 , 28 , 29 , 30 ].…”

Section: General Mechanism and Feature Of Antibody–antigen Recognitionmentioning

confidence: 99%

Recent Progress in Antibody Epitope Prediction

et al. 2023

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Recent progress in epitope prediction has shown promising results in the development of vaccines and therapeutics against various diseases. However, the overall accuracy and success rate need to be improved greatly to gain practical application significance, especially conformational epitope prediction. In this review, we examined the general features of antibody–antigen recognition, highlighting the conformation selection mechanism in flexible antibody–antigen binding. We recently highlighted the success and warning signs of antibody epitope predictions, including linear and conformation epitope predictions. While deep learning-based models gradually outperform traditional feature-based machine learning, sequence and structure features still provide insight into antibody–antigen recognition problems.

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Antigen binding by conformational selection in near-germline antibodies

Cited by 5 publications

References 65 publications

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS‐CoV‐2

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS‐CoV‐2

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2

Recent Progress in Antibody Epitope Prediction

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