Exploring the conformational heterogeneity of biomolecules: Theory and experiments

The atomic constituents of matter move continuously. Irrespective of the physical state, their kinetic energy is of the order of kT, which amounts to about 3 kJ mol−1 at room temperature. Besides local motions, which always occur, biomolecules in solution can sample many different conformations, which can even be largely different from one another, provided these conformations have comparable energies and the energetic barriers among them for the interconversion are not much higher than kT. Intrinsically disordered proteins (IDPs) are the most striking example. For IDPs the very term “structure” is meaningless. Multidomain proteins may be constituted by well-structured domains but, if the domains are connected by flexible linkers, their reciprocal spatial arrangement may be as undetermined as the spatial arrangement of the individual residues in IDPs. Even single-domain, globular proteins can undergo large movements of secondary structure elements, leading to two or more conformers whose structures may differ significantly. Obviously, this dynamic behavior may greatly affect the function in vivo. Nucleic acids, both DNA and RNA, behave similarly, and it is still largely unknown how their conformational heterogeneity may vitally affect transcription and translation processes. Although certainly not exhaustive, the present issue contains a very valuable collection of timely papers that hopefully will contribute to the clarification of some misunderstandings about what can and cannot be obtained on disordered systems, will provide some interesting new examples of systems of this type, and will stimulate further research in this challenging and important field.