Conservation of intrinsic dynamics in proteins — what have computational models taught us?

Tiwari, Sandhya; Reuter, Nathalie

doi:10.1016/j.sbi.2017.12.001

Cited by 40 publications

(33 citation statements)

References 69 publications

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“…Interestingly, the β4 and β5 strands carry residues involved in the proton wire essential for the transfer of the acetyl. The rigidity of the catalytic core in the GNAT fold is in agreement with case-studies of enzyme dynamics where residues involved in catalysis are found to be placed at rigid conserved positions of the fold thus stabilizing amino acids essential for the function [33,56,58].…”

Section: Discussionsupporting

confidence: 78%

“…Similarity in fold or topology is generally associated with similarity in flexibility and dynamics [33,56]. We here intend to characterize the flexibility intrinsic to the topology of the GNAT fold.…”

Section: Resultsmentioning

confidence: 99%

“…The most mobile regions in NATs are the functional loops α1α2, β3β4 and β6β7. Substrate-binding residues have a tendency to be in more flexible regions than catalytic residues [56,68,69] and the α1α2 and β6β7 loops carry residues involved in substrate binding [19]. The C-terminal end of helix α2 has been identified as carrying a mutation (p. S37P) in the human Naa10 that is causative of the lethal Ogden syndrome [4].…”

Section: Discussionmentioning

confidence: 99%

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Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

Abboud

Bedoucha

Arnesen

et al. 2018

Preprint

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23 N-terminal acetyltransferases (NATs) are enzymes catalysing the transfer of the acetyl from Ac-CoA to the 24 N-terminus of proteins, one of the most common protein modifications. Unlike NATs, lysine 25 acetyltransferases (KATs) transfer an acetyl onto the amine group of internal lysines. To date, not much is 26 known on the exclusive substrate specificity of NATs towards protein N-termini. All the NATs and some 27 KATs share a common fold called GNAT. The main difference between NATs and KATs is an extra 28 hairpin loop found only in NATs called β6β7 loop. It covers the active site as a lid. The hypothesized role of 29 the loop is that of a barrier restricting the access to the catalytic site and preventing acetylation of internal 30 lysines. We investigated the dynamics-function relationships of all available structures of NATs covering 31 the three domains of life. Using elastic network models and normal mode analysis, we found a common 32 dynamics pattern conserved through the GNAT fold; a rigid V-shaped groove, formed by the β4 and β5 33 strands and three relatively more dynamic loops α1α2, β3β4 and β6β7. We identified two independent 34 dynamical domains in the GNAT fold, which is split at the β5 strand. We characterized the β6β7 hairpin 35 loop slow dynamics and show that its movements are able to significantly widen the mouth of the ligand 36 binding site thereby influencing its size and shape. Taken together our results show that NATs may have 37 access to a broader ligand specificity range than anticipated. 38Author summary 39 N-terminal acetylation concerns 80% of eukaryotic proteins and is achieved by enzymes called the 40 N-terminal acetyltransferases (NATs). They belong to the large family of acetyltransferases and 41 adopt the GNAT fold. Interestingly most lysine acetyltransferases (KATs), which acetylate 42 specifically internal lysines, share the same fold. Rationale for the ligand recognition by the GNAT 43 enzymes remains unclear. Proteins are dynamic entities that utilize their structural flexibility to 44 carry out functions in living cells. By studying the dynamics throughout the entire NATs family, 45 we found that the slow dynamics of the fold is strongly conserved. We also revealed the mobility of 46 the active site lid, namely the -hairpin loop 67, which is one of the main structural differences between 47 the NATs and the KATs. The size and shape of the ligand binding site depend on movements of that -Dynamics-function relationship of NATs 3 48 hairpin loop. We suggest that in attempts of mapping NATs specificity or ligand design the fold flexibility 49 should be taken into consideration. 50 51 Acetyltransferases are enzymes catalysing the transfer of an acetyl group from the co-factor acetyl-52 coenzyme A (Ac-CoA) to a substrate. Among them, lysine acetyltransferases (KATs) and Nα-terminal 53 acetyltransferases (NATs) perform protein acetylation to either lysine side chains or N-termini of 54 polypeptide chains, respectively. NATs acetylate 80 to 90% of the proteins of the human ...

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

Abboud

Bedoucha

Arnesen

et al. 2018

Preprint

Self Cite

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“…Classic all-atom Molecular Dynamics (MD) simulations represent a common strategy, sometimes combined with experimental approaches [18][19] , which can however be computationally costly when working on large systems or modeling events taking place on a long time-scale 20 . Another option is to use coarse-grain models, that combine simplified protein representations and energy functions [21][22][23] . In that perspective, we initially developed the ProPHet (Probing Protein Heterogeneity) program, which models proteins as an elastic network, to investigate protein mechanical properties on the residue level 24 .…”

Section: Introductionmentioning

confidence: 99%

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

Sacquin-Mora

2019

Preprint

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Dynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein's internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all atom classic molecular dynamics simulations and coarse grain calculations of the resulting conformational ensemble mechanical properties. Here we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.! 2

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“…Sequence and structure comparison algorithms are long‐standing techniques in proteins research . In recent years, several tools and techniques have been developed for comparison of protein dynamics and contributed to the development of the field of comparative dynamics …”

Section: Introductionmentioning

confidence: 99%

Dynamical comparison between myoglobin and hemoglobin

Aharoni

Tobi

2018

Proteins

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Myoglobin and hemoglobin are globular hemeproteins, when the former is a monomer and the latter a heterotetramer. Despite the structural similarity of myoglobin to α and β subunits of hemoglobin, there is a functional difference between the two proteins, owing to the quaternary structure of hemoglobin. The effect of the quaternary structure of hemoglobin on the intrinsic dynamics of its subunits is explored by dynamical comparison of the two proteins. Anisotropic Network Model modes of motion were calculated for hemoglobin and myoglobin. Dynamical comparison between the proteins was performed using global and local Anisotropic Network Model mode alignment algorithms based on the algorithms of Smith-Waterman and Needleman-Wunsch for sequence comparison. The results indicate that the quaternary structure of hemoglobin substantially alters the intrinsic dynamics of its subunits, an effect that may contribute to the functional difference between the two proteins. Local dynamics similarity between the proteins is still observed at the major exit route of the ligand.

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Conservation of intrinsic dynamics in proteins — what have computational models taught us?

Cited by 40 publications

References 69 publications

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

Dynamical comparison between myoglobin and hemoglobin

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