Biomolecular structures: from isolated molecules to the cell crowded medium

A sizeable fraction of biomolecules fold into well-defined 3-D conformations in the cellular medium. Since structures and functions are generally considered as intimately related, a considerable effort has thus been devoted to the determination of biomolecular conformations under different conditions. The intracellular medium is highly heterogeneous and crowded. Thus, for simplicity, most structural studies have usually been conducted under well-defined and homogeneous conditions. For example, purified proteins have for many years been investigated by means of X-ray crystallography in single crystals or through NMR in rather dilute solutions.

In parallel, modelling of biomolecules has been developed at different levels of theory according to the size of the considered systems. Ab initio and Density Functional Theory methods have been applied to elementary building blocks (amino acids, nucleobases or sugars) while coarse-grained methods were developed for extremely large systems, ignoring atomic details at that point. The gap between those extreme situations is filled by semi-empirical approaches and force-fields. For many years, it was difficult to directly compare quantum predictions of structures to experimental results. Today, three disciplines that had previously evolved almost independently have actively started merging. Experimentally, it is now common practice to couple mass spectrometry to spectroscopy, thus allowing the recording of well-resolved spectra of biomolecular building blocks isolated in the gas phase. Conditions are then fulfilled for accurate comparison between predictions of quantum chemistry and experimental data. Well-established techniques developed by the mass-spectrometry community, such as electrospray, as well as new sources capable of delivering intact non-volatile species and their non-covalent complexes either at extremely low temperature or at room temperature are used in combination with table-top or free electron lasers as well as synchrotron radiation. In turn, use of mass spectrometry in biological applications such as proteomics benefits from a deeper knowledge of fragmentation mechanisms. Ideal gas-phase and more realistic solution-phase structures no longer belong to widely separated research domains and today are often compared. Folding properties of proteins can nowadays be modelled under the crowded situation encountered in living cells.

This Themed Issue covers a wide range of different state-of-the-art experimental and theoretical approaches to the determination of biomolecular structures. The need for theoretical methods that are both accurate and computer-time efficient has prompted the recent appearance of new modelling techniques which can be applied as well to the gas phase (Morgado et al., DOI: 10.039/b924461a; Cimas and Gaigeot, DOI: 10.039/b924025j; Toroz and van Mourik, DOI: 10.039/b921897a; Semrouni et al., DOI: 10.1039/b924317h) as to the aqueous phase (Furmanchuk et al., DOI: 10.039/b923930h) and to crowded cellular conditions (Tsao et al., DOI: 10.039/b924236h).

A wide variety of experimental spectroscopic determinations of structures of gas-phase isolated biomolecular systems interpreted with the help of quantum calculations cover a very wide spectral range, from the microwave (Sanz et al., DOI: 10.039/b926520a) and infrared (Carl et al., DOI: 10.039/b919039b; Cagmat et al., DOI: 10.039/b924027f; Marta et al., DOI: 10.039/b921102k; Ganim et al., DOI: 10.039/b923515a; Poully et al., DOI: 10.039/b923630a; de Vries et al., DOI: 10.039/b925340h) up to the UV and VUV (Compagnon et al., DOI: 10.039/b922514p; Ko et al., DOI: 10.039/b924950h; Aravind et al., DOI: 10.039/b921038e; Holm et al., DOI: 10.039/b924076d; Poully et al.) regions. Instead of photon absorption, electron capture from ions (Bari et al., DOI: 10.039/b924145k) and their photo-removal (Compagnon et al., Ko et al.) also provides a wealth of information. Networks of elementary biomolecular building blocks can be self-assembled on graphite and their structures then become observable through scanning tunnelling microscopy (Bald et al., DOI: 10.1039/b924098e).

Determination of structures of large biomolecular complexes involving membrane proteins can be very difficult. The development of a new mass-spectrometry source offers the possibility to assess the quaternary structures of those proteins and their complexes directly from the solution phase (Hoffmann et al., DOI: 10.039/b924630d).

The structural role of solvation, in particular hydration, can be investigated either by step-wise addition of water molecules (Calvo and Douady, DOI: 10.039/b923972c; Pincu et al., DOI: 10.039/b925797g; Zhu et al., DOI: 10.039/b926413b; Kokubu et al., DOI: 10.1039/b924822f; Gerhards et al., DOI: 10.039/c000424c) or directly in bulk solvents (Ganim et al.). The influence of both hydration and temperature upon conformational dynamics and flexibility is reviewed in the case of floppy peptides (Gaigeot, DOI: 10.039/b924048a). Dynamical studies complement structural determinations since the folding and unfolding of proteins are crucial for their bioactivity (Liu et al., DOI: 10.039/b925033f; Jasnin et al.; Ganim et al.).

Complementary to model studies of biomolecular building blocks, the structural determination of biomolecular systems such as heparan sulphate (Jasnin et al., DOI: 10.039/b923878f), insulin (Ganim et al.), vancomycin (Grégoire et al., DOI: 10.039/b923787a), defensin inspired peptides (McCullough et al., DOI: 10.1039/b923784d), neocarzinostatin (Wang and Merz, DOI: 10.039/b924951f) and amyloid peptide (Shea et al., DOI: 10.039/c000755m) is directly relevant to pharmaceutical and medical problems.

Seong Keun Kim, Department of Chemistry and Department of Biophysics and Biochemical Chemistry, Seoul National University, Korea

Taekjip Ha, University of Illinois at Urbana Champaign, USA; Howard Hughes Medical Institute, USA; Seoul National University, Korea

Jean-Pierre Schermann, Université Paris 13, France; WCU Department of Biophysics and Biochemical Chemistry, Seoul National University, Korea

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