The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

Elena Papaleo*, Giorgio Saladino, Matteo Lambrughi, Kresten Lindorff-Larsen, Francesco Luigi Gervasio, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

273 Scopus citations


Proteins are dynamic entities that undergo a plethora of conformational changes that may take place on a wide range of time scales. These changes can be as small as the rotation of one or a few side-chain dihedral angles or involve concerted motions in larger portions of the three-dimensional structure; both kinds of motions can be important for biological function and allostery. It is becoming increasingly evident that "connector regions" are important components of the dynamic personality of protein structures. These regions may be either disordered loops, i.e., poorly structured regions connecting secondary structural elements, or linkers that connect entire protein domains. Experimental and computational studies have, however, revealed that these regions are not mere connectors, and their role in allostery and conformational changes has been emerging in the last few decades. Here we provide a detailed overview of the structural properties and classification of loops and linkers, as well as a discussion of the main computational methods employed to investigate their function and dynamical properties. We also describe their importance for protein dynamics and allostery using as examples key proteins in cellular biology and human diseases such as kinases, ubiquitinating enzymes, and transcription factors.

Original languageEnglish
Pages (from-to)6391-6423
Number of pages33
JournalChemical Reviews
Issue number11
StatePublished - 8 Jun 2016


FundersFunder number
National Cancer InstituteZIABC010441
Engineering and Physical Sciences Research CouncilEP/M013898/1


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