Global and local indices for characterizing biomolecular flexibility and rigidity

Understanding flexibility and rigidity characteristics of biomolecules is a prerequisite for understanding biomolecular structural stability and function. Computational methods have been implemented that directly characterize biomolecular flexibility and rigidity by constraint network analysis. For deriving maximal advantage from these analyses, their results need to be linked to biologically relevant characteristics of a structure. Such links are provided by global and local measures (“indices”) of biomolecular flexibility and rigidity. To date, more than 14 indices are available with sometimes overlapping or only vague definitions. We present concise definitions of these indices, analyze the relation between, and the scope and limitations of them, and compare their informative value. For this, we probe the structural stability of the calcium binding protein α‐lactalbumin as a showcase, both in the “ground state” and after perturbing the system by changing the network topology. In addition, we introduce three indices for the first time that extend the application domain of flexibility and rigidity analyses. The results allow us to provide guidelines for future studies suggesting which of these indices could best be used for analyzing, understanding, and quantifying structural features that are important for biomolecular stability and function. Finally, we make suggestions for proper index notations in future studies to prevent the misinterpretation and to facilitate the comparison of results obtained from flexibility and rigidity analyses. © 2012 Wiley Periodicals, Inc. Being able to describe biomolecular flexibility and rigidity is essential for understanding their stability and function. Computational methods have been implemented that directly characterize biomolecular flexibility and rigidity by constraint network analysis (CNA). Here, concise definitions of existing and new indices derived from CNA are presented, the relation between, and the scope and limitations of them analyzed, and their informative value compared. As a showcase, the structural stability of the calcium binding protein α‐lactalbumin is probed.