Protein flexibility in the light of structural alphabets

Abstract

Protein structures are valuable tools to understand protein function. Nonetheless, proteins are often considered as rigid macromolecules while their structures exhibit specific flexibility, which is essential to complete their functions. Analyses of protein structures and dynamics are often performed with a simplified three-state description, i.e., the classical secondary structures. More precise and complete description of protein backbone conformation can be obtained using libraries of small protein fragments that are able to approximate every part of protein structures. These libraries, called structural alphabets (SAs), have been widely used in structure analysis field, from definition of ligand binding sites to superimposition of protein structures. SAs are also well suited to analyze the dynamics of protein structures. Here, we review innovative approaches that investigate protein flexibility based on SAs description. Coupled to various sources of experimental data (e.g., B-factor) and computational methodology (e.g., Molecular Dynamic simulation), SAs turn out to be powerful tools to analyze protein dynamics, e.g., to examine allosteric mechanisms in large set of structures in complexes, to identify order/disorder transition. SAs were also shown to be quite efficient to predict protein flexibility from amino-acid sequence. Finally, in this review, we exemplify the interest of SAs for studying flexibility with different cases of proteins implicated in pathologies and diseases.

The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

“…We then wondered if these differences could be due to local conformational variabilities in the structures sampled by each simulation. To this aim, we exploited the structural alphabet (SA) paradigm (Craveur et al, 2015) to estimate the sampling of local states in the simulations, relying on a reduced version of the M32K25 structural alphabet (Pandini et al, 2010) (A, K, U, R, N and Y, as detailed in Methods and Figure 3C). At first, we estimated the discrete probability distribution of the states for each fragment of the protein in the different MD ensembles.…”

Solubility-Weighted Index: fast and accurate prediction of protein solubility

“…In this study, we investigated the experimental outcomes of 12,216 recombinant proteins expressed in Escherichia coli from the 'Protein Structure Initiative:Biology' (PSI:Biology) (Chen et al 2004;Acton et al 2005) . We showed that protein structural flexibility is more accurate than other protein sequence properties in predicting solubility (Craveur et al 2015;M. Vihinen, Torkkila, and Riikonen 1994) .…”

Structural basis for dimer formation of the CRISPR‐associated protein Csm2 of Thermotoga maritima

“…Additionally these loops, together with the N-terminal helices and contrasting with the large a-helices, have a higher than average B-factor distribution, indicating that they could be involved in ligand binding, as intrinsic flexibility is thought to be important in DNA binding proteins [37,38]. However, as fitting of crystal structures to electron microscopy electron density maps is not trivial, these electron density maps are derived from different species and furthermore the number of Csm2 homologues detected in mass spectrometry data in crRNP complexes from these different species corresponds most probably to 3 subunits [18,28], this evidence must be regarded as preliminary.…”

“…As the Csm2 surface on the side with positive electrostatic potential forms a channel between the small a-helices, and the sequence of the loops forming this channel (located between helices H1 and H2) shows a higher than average degree of conservation in all three species, it is tempting to speculate that this channel is of high functional importance for example participating in the binding of target oligonucleotide bases. Additionally these loops, together with the N-terminal helices and contrasting with the large a-helices, have a higher than average B-factor distribution, indicating that they could be involved in ligand binding, as intrinsic flexibility is thought to be important in DNA binding proteins [37,38]. However, as fitting of crystal structures to electron microscopy electron density maps is not trivial, these electron density maps are derived from different species and furthermore the number of Csm2 homologues detected in mass spectrometry data in crRNP complexes from these different species corresponds most probably to 3 subunits [18,28], this evidence must be regarded as preliminary.…”