Flexibility of α-Helices: Results of a Statistical Analysis of Database Protein Structures

Abstract

Alpha-helices stand out as common and relatively invariant secondary structural elements of proteins. However, alpha-helices are not rigid bodies and their deformations can be significant in protein function (e.g. coiled coils). To quantify the flexibility of alpha-helices we have performed a structural principal-component analysis of helices of different lengths from a representative set of protein folds in the Protein Data Bank. We find three dominant modes of flexibility: two degenerate bend modes and one twist mode. The data are consistent with independent Gaussian distributions for each mode. The mode eigenvalues, which measure flexibility, follow simple scaling forms as a function of helix length. The dominant bend and twist modes and their harmonics are reproduced by a simple spring model, which incorporates hydrogen-bonding and excluded volume. As an application, we examine the amount of bend and twist in helices making up all coiled-coil proteins in SCOP. Incorporation of alpha-helix flexibility into structure refinement and design is discussed.

Consequences of domain insertion on sequence-structure divergence in a superfold

“…S12) that was used to select an appropriate cutoff for the number of columns (L = 132). Similar to Emberly et al (43), all of the structures were realigned to the "center" structure (2HSZ, chain A). We created an N × 3L coordinate matrix, where each row represents individual structures and each column represents C α -coordinates of the amino acid residues from the columns in the MSA.…”

Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins

“…35,41,42 It has also been hypothesized that collective correlated motions derived from MD simulations may be employed to identify structural subunits (domains) in proteins and assess local flexibility. [43][44][45] However, not all the results available in the literature are straightforward to reproduce or interpret because of a broad variety of model assumptions, protocols and sampling schemes. 46 These wide variations exist, in part, because a systematic theoretical framework has been absent until recently.…”

“…In particular, the identification of domains would typically require either a priori assumptions regarding the protein's domain structures, or the use of a hypothetical reference frame, 43 whereas the assessment of the local flexibility would typically be limited to a statistical analysis of average residue displacements. [43][44][45] Recently, a novel theoretical formalism has been developed in our group to analyze collective coarse-grained dynamics in proteins. 47 This approach allows one to readily identify long term collective motions in a large molecule.…”

New Advances in Normal Mode Analysis of Supermolecular Complexes and Applications to Structural Refinement

“…For example, a particular structural component in a complex, such as a subunit or a secondary structural element, can deform along its own intrinsic normal modes (which can be determined when the structural element is in isolation) in a harmonic fashion, but gets locked in its deformed conformation by surrounding interactions statically in the complex. A good example [51] is provided by a principal-component analysis of the flexibility of α-helices in all coiled-coil proteins in the SCOP database [52]. Although every α-helix in these systems is in a permanently deformed state, it was found that the principal modes (bending and twisting modes) determined from the ensemble of all static snapshots are in extremely good agreement with the dynamic normal modes.…”

“…Moreover, one must note that it is easy to misinterpret the hidden harmonic nature of the molecular deformations depending on how the analysis is carried out. If one analyzes the system including the interested structural components plus their interacting neighbors, it may very well appear to be that the conformational changes are not harmonic as in the cases of those permanently deformed α-helices [51]. But if one separates the interested structural components from the surrounding locking interactions, the harmonic nature of the conformational changes could become evident.…”