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.

Peptide bonds in protein structures are mainly found in trans conformation with a torsion angle ω close to 180°. Only a very low proportion is observed in cis conformation with ω angle around 0°. Cis-trans isomerization leads to local conformation changes which play an important role in many biological processes. In this paper, we reviewed the recent discoveries and research achievements in this field. First, we presented some interesting cases of biological processes in which cis-trans isomerization is directly implicated. It is involved in protein folding and various aspect of protein function like dimerization interfaces, autoinhibition control, channel gating, membrane binding. Then we reviewed conservation studies of cis peptide bonds which emphasized evolution constraints in term of sequence and local conformation. Finally we made an overview of the numerous molecular dynamics studies and prediction methodologies already developed to take into account this structural feature in the research area of protein modeling. Many cis peptide bonds have not been recognized as such due to the limited resolution of the data and to the refinement protocol used. Cis-trans proline isomerization reactions represents a vast and promising research area that still needs to be further explored for a better understanding of isomerization mechanism and improvement of cis peptide bond predictions.