Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

Radjasandirane, Ragousandirane; Brevern, Alexandre G. de

doi:10.3390/biom13030509

Cited by 3 publications

(1 citation statement)

References 92 publications

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“…Obtained through an unsupervised training approach and performed on a representative, non-redundant databank, PBs give a reasonable approximation of all local protein 3D structures [60]. PBs are very efficient in tasks such as protein superimpositions [61,62] and MD analyses [63,64]. They are labeled from a to p: PBs m and d can be roughly described as prototypes for α-helix and central β-strand, respectively.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Potential Impact of In Silico Humanization on VHH Dynamics

Martins,

Diharce,

Nadaradjane

et al. 2023

IJMS

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Camelids have the peculiarity of having classical antibodies composed of heavy and light chains as well as single-chain antibodies. They have lost their light chains and one heavy-chain domain. This evolutionary feature means that their terminal heavy-chain domain, VH, called VHH here, has no partner and forms an independent domain. The VHH is small and easy to express alone; it retains thermodynamic and interaction properties. Consequently, VHHs have garnered significant interest from both biotechnological and pharmaceutical perspectives. However, due to their origin in camelids, they cannot be used directly on humans. A humanization step is needed before a possible use. However, changes, even in the constant parts of the antibodies, can lead to a loss of quality. A dedicated tool, Llamanade, has recently been made available to the scientific community. In a previous paper, we already showed the different types of VHH dynamics. Here, we have selected a representative VHH and tested two humanization hypotheses to accurately assess the potential impact of these changes. This example shows that despite the non-negligible change (1/10th of residues) brought about by humanization, the effect is not drastic, and the humanized VHH retains conformational properties quite similar to those of the camelid VHH.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Potential Impact of In Silico Humanization on VHH Dynamics

Martins,

Diharce,

Nadaradjane

et al. 2023

IJMS

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Influence of Stereochemistry in a Local Approach for Calculating Protein Conformations

da Rocha,

Liberti,

Mucherino

et al. 2024

J. Chem. Inf. Model.

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Protein structure prediction is generally based on the use of local conformational information coupled with longrange distance restraints. Such restraints can be derived from the knowledge of a template structure or the analysis of protein sequence alignment in the framework of models arising from the physics of disordered systems. The accuracy of approaches based on sequence alignment, however, is limited in the case where the number of aligned sequences is small. Here, we derive protein conformations using only local conformations knowledge by means of the interval Branch-and-Prune algorithm. The computation efficiency is directly related to the knowledge of stereochemistry (bond angle and ω values) along the protein sequence and, in particular, to the variations of the torsion angle ω. The impact of stereochemistry variations is particularly strong in the case of protein topologies defined from numerous long-range restraints, as in the case of protein of β secondary structures. The systematic enumeration of the conformations improves the efficiency of the calculations. The analysis of DNA codons permits to connect the variations of torsion angle ω to the positions of rare DNA codons.

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A Simple Analysis of the Second (Extra) Disulfide Bridge of VHHs

Martins,

Gardebien,

Nadaradjane

et al. 2024

Molecules

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Camelids produce a special type of antibody, known as VHHs, that has lost the VL domain, providing a more optimised VH domain. This particular highly stable antibody domain has interesting properties for biotechnological development. Ordinarily, those molecules possess only one disulphide bridge, but surprisingly, at least a quarter of these VHHs have a second one. Curiously, this does not seem to be essential for the stability and the function of this domain. In an attempt to characterise precisely the role and impact of this disulphide bridge at the molecular level, several in silico mutants of a VHH were created to disrupt this second disulphide bridge and those systems were submitted to molecular dynamics simulation. The loss of the second disulphide bridge leads to an increase in the flexibility of CDR1 and CDR3 and an unexpected rigidification of CDR2. Local conformational analysis shows local differences in the observed protein conformations. However, in fact, there is no exploration of new conformations but a change in the equilibrium between the different observed conformations. This explains why the interaction of VHHs is not really affected by the presence or absence of this second bridge, but their rigidity is slightly reduced. Therefore, the additional disulphide bridge does not seem to be an essential part of VHHs function.

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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

Cited by 3 publications

References 92 publications

Evaluation of the Potential Impact of In Silico Humanization on VHH Dynamics

Evaluation of the Potential Impact of In Silico Humanization on VHH Dynamics

Influence of Stereochemistry in a Local Approach for Calculating Protein Conformations

A Simple Analysis of the Second (Extra) Disulfide Bridge of VHHs

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