Here, we extend the analysis to -sheet flexibility using PCA on a data-base of -sheet structures. Recent work has quantified the flexibility of -helices using a principal component analysis (PCA) of database helical structures (J. Neither structure is rigid, and the flexibility of helices and sheets is often important in determining the final fold (e.g., coiled coils and -barrels). In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function.ĪBSTRACT Protein folds are built primarily from the packing together of two types of struc-tures: -helices and -sheets. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl-prolyl isomerization catalyzed by the enzyme cyclophilin A. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub-states. QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Methods and Findings: To overcome these challenges we have developed a new computational technique, quasi-anharmonic analysis (QAA). However, low populations in these sub-states and the transient nature of conformational transitions between these sub-states present significant challenges for their identification and characterization. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant.
The role of conformational fluctuations in the designated function of a protein is widely debated. Background: Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state.
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