In silico prediction of protein flexibility with local structure approach

Narwani, Tarun Jairaj; Etchebest, Catherine; Craveur, Pierrick; Léonard, Sylvain; Rebehmed, Joseph; Srinivasan, Narayanaswamy; Bornot, Aurélie; Gelly, Jean‐Christophe; Brevern, Alexandre G. de

doi:10.1016/j.biochi.2019.07.025

Cited by 17 publications

(7 citation statements)

References 30 publications

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“…The first region is 11 residues long (positions 763–775) whereas the second one is 34 residues long (positions 840–873). The second region is long enough to be beyond the scope of default loop-modelling algorithms [ 21 ], with no repetitive secondary structure [ 22 , 23 ] and high flexibility content [ 24 , 25 , 26 ]. To expertly model these, sequence homologs were mined using PSI-BLAST [ 27 ] and structurally similar molecules were identified using the FATCAT algorithm (Flexible structure AlignmenT by Chaining Aligned fragment pairs allowing Twists) [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

Anies

Jallu²,

Diharce

et al. 2022

IJMS

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Integrin αIIbβ3, a glycoprotein complex expressed at the platelet surface, is involved in platelet aggregation and contributes to primary haemostasis. Several integrin αIIbβ3 polymorphisms prevent the aggregation that causes haemorrhagic syndromes, such as Glanzmann thrombasthenia (GT). Access to 3D structure allows understanding the structural effects of polymorphisms related to GT. In a previous analysis using Molecular Dynamics (MD) simulations of αIIb Calf-1 domain structure, it was observed that GT associated with single amino acid variation affects distant loops, but not the mutated position. In this study, experiments are extended to Calf-1, Thigh, and Calf-2 domains. Two loops in Calf-2 are unstructured and therefore are modelled expertly using biophysical restraints. Surprisingly, MD revealed the presence of rigid zones in these loops. Detailed analysis with structural alphabet, the Proteins Blocks (PBs), allowed observing local changes in highly flexible regions. The variant P741R located at C-terminal of Calf-1 revealed that the Calf-2 presence did not affect the results obtained with isolated Calf-1 domain. Simulations for Calf- 1+ Calf-2, and Thigh + Calf-1 variant systems are designed to comprehend the impact of five single amino acid variations in these domains. Distant conformational changes are observed, thus highlighting the potential role of allostery in the structural basis of GT.

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Section: Resultsmentioning

confidence: 99%

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

Anies

Jallu²,

Diharce

et al. 2022

IJMS

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“…Analysis of RMSF (see Figures 2B, 3B and S3B) shows high values in RMSF in the CDRs (63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74). Interestingly, the FR2 region (46)(47)(48)(49)(50)(51)(52) and FR3 (77-79 and 89-95) are also associated with high values. At first glance, the whole of FR2 (18 residues) is highly flexible except for two regions between 44-47 and 55-63.…”

Section: Flexibility At Each Residue Positionmentioning

confidence: 98%

“…It describes more precisely the local conformation [44]. The PB alignment shown in Figure 1C represents the corresponding PB assignment at each residue position of a given V H H domain aligned according to the MSA, where 10-20% diversity is observed in FR1 (positions 3-25), FR2 (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62) and FR3 (77-113) regions, especially in the loop between the β-stands (represented by the Protein Block d). The PB analysis shows no residue is associated with the coil state.…”

Section: Dataset Descriptionmentioning

confidence: 99%

General Trends of the Camelidae Antibody VHHs Domain Dynamics

Vattekatte

Diharce

Rebehmed

et al. 2023

IJMS

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Conformational flexibility plays an essential role in antibodies’ functional and structural stability. They facilitate and determine the strength of antigen–antibody interactions. Camelidae express an interesting subtype of single-chain antibody, named Heavy Chain only Antibody. They have only one N-terminal Variable domain (VHH) per chain, composed of Frameworks (FRs) and Complementarity Determining regions (CDRs) like their VH and VL counterparts in IgG. Even when expressed independently, VHH domains display excellent solubility and (thermo)stability, which helps them to retain their impressive interaction capabilities. Sequence and structural features of VHH domains contributing to these abilities have already been studied compared to classical antibodies. To have the broadest view and understand the changes in dynamics of these macromolecules, large-scale molecular dynamics simulations for a large number of non-redundant VHH structures have been performed for the first time. This analysis reveals the most prevalent movements in these domains. It reveals the four main classes of VHHs dynamics. Diverse local changes were observed in CDRs with various intensities. Similarly, different types of constraints were observed in CDRs, while FRs close to CDRs were sometimes primarily impacted. This study sheds light on the changes in flexibility in different regions of VHH that may impact their in silico design.

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“…They can be divided into two main types: prediction of residue flexibility and prediction of a protein's structural ensemble. Individual residue flexibility can be predicted using many techniques including information from crystallographic B-factors (Schlessinger and Rost, 2005), normal mode analysis (NMA) (Jacobs et al, 2001), NMR chemical shift data (Cilia et al, 2014) and Molecular Dynamics (MD) simulation data (Narwani et al, 2019). While some of these methods can predict residue flexibility from sequence alone, the predictions contain no information about different distinct conformations of a protein.…”

Section: Introductionmentioning

confidence: 99%

Co-evolutionary distance predictions contain flexibility information

Schwarz

Georges²,

Kelm

et al. 2021

Bioinformatics

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Motivation Co-evolution analysis can be used to accurately predict residue-residue contacts from multiple sequence alignments. The introduction of machine-learning techniques has enabled substantial improvements in precision and a shift from predicting binary contacts to predicting distances between pairs of residues. These developments have significantly improved the accuracy of de novo prediction of static protein structures. With AlphaFold2 lifting the accuracy of some predicted protein models close to experimental levels, structure prediction research will move on to other challenges. One of those areas is the prediction of more than one conformation of a protein. Here we examine the potential of residue-residue distance predictions to be informative of protein flexibility rather than simply static structure. Results We used DMPfold to predict distance distributions for every residue pair in a set of proteins that showed both rigid and flexible behaviour. Residue pairs that were in contact in at least one reference structure were classified as rigid, flexible or neither. The predicted distance distribution of each residue pair was analysed for local maxima of probability indicating the most likely distance or distances between a pair of residues. We found that rigid residue pairs tended to have only a single local maximum in their predicted distance distributions while flexible residue pairs more often had multiple local maxima. These results suggest that the shape of predicted distance distributions contains information on the rigidity or flexibility of a protein and its constituent residues. Supplementary information Supplementary data are available at Bioinformatics online.

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In silico prediction of protein flexibility with local structure approach

Cited by 17 publications

References 30 publications

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

General Trends of the Camelidae Antibody VHHs Domain Dynamics

Co-evolutionary distance predictions contain flexibility information

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