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.

Centre National de la Recherche Scientifique UMR7590 Sorbonne Universités Université Pierre et Marie Curie MNHN IRD IUC Paris France

Institut National de la Santé et de la Recherche Médicale U 1134 Paris France ; Institut National de la Transfusion Sanguine DSIMB Paris France ; UMR_S 1134 DSIMB Laboratory of Excellence GR Ex Paris France

Institut National de la Santé et de la Recherche Médicale U 1134 Paris France ; UMR_S 1134 DSIMB Université Paris Diderot Sorbonne Paris Cite Paris France ; Institut National de la Transfusion Sanguine DSIMB Paris France ; UMR_S 1134 DSIMB Laboratory of Excellence GR Ex Paris France

Institut National de la Santé et de la Recherche Médicale U 1134 Paris France ; UMR_S 1134 DSIMB Université Paris Diderot Sorbonne Paris Cite Paris France ; Institut National de la Transfusion Sanguine DSIMB Paris France ; UMR_S 1134 DSIMB Laboratory of Excellence GR Ex Paris France ; Ets Poulain Pointe Noire Congo

Institut National de la Santé et de la Recherche Médicale U 1134 Paris France ; UMR_S 1134 DSIMB Université Paris Diderot Sorbonne Paris Cite Paris France ; Institut National de la Transfusion Sanguine DSIMB Paris France ; UMR_S 1134 DSIMB Laboratory of Excellence GR Ex Paris France ; Faculté des Sciences et Techniques Université de Nantes Unité Fonctionnalité et Ingénierie des Protéines Centre National de la Recherche Scientifique UMR 6286 Université Nantes Nantes France

Institut National de la Santé et de la Recherche Médicale U 1134 Paris France ; UMR_S 1134 DSIMB Université Paris Diderot Sorbonne Paris Cite Paris France ; Institut National de la Transfusion Sanguine DSIMB Paris France ; UMR_S 1134 DSIMB Laboratory of Excellence GR Ex Paris France ; Laboratoire de Physique École Normale Supérieure de Lyon Université de Lyon Centre National de la Recherche Scientifique UMR 5672 Lyon France

Institut National de la Santé et de la Recherche Médicale U964 7 UMR Centre National de la Recherche Scientifique 7104 IGBMC Université de Strasbourg Illkirch France

Institute of Biotechnology The Czech Academy of Sciences Prague Czech Republic

Metagenopolis INRA Jouy en Josas France

Molecular Biophysics Unit Indian Institute of Science Bangalore Bangalore India

Molecular Biophysics Unit Indian Institute of Science Bangalore Bangalore India ; Department of Theoretical Biophysics Max Planck Institute of Biophysics Frankfurt Germany

Molecular Biophysics Unit Indian Institute of Science Bangalore Bangalore India ; Hospital for Sick Children and Departments of Biochemistry and Molecular Genetics University of Toronto Toronto ON Canada

National Library of Medicine National Center for Biotechnology Information National Institutes of Health Bethesda MD USA

Platelet Unit Institut National de la Transfusion Sanguine Paris France

Rutherford Appleton Laboratory Science and Technology Facilities Council Didcot UK

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The LILI Motif of M3-S2 Linkers Is a Component of the NMDA Receptor Channel Gate