authoritative, comprehensive and systematic

Alternative splicing of intrinsically disordered regions and rewiring of protein interactions

Structure-based studies of chemokine receptors

Theory and simulation

Computational methods for high resolution prediction and refinement of protein structures

Structure- and sequence-analysis inspired engineering of proteins for enhanced thermostability

Prediction of contacts from correlated sequence substitutions

Generation of functional antibodies for mammalian membrane protein crystallography

Macromolecular assemblies

Protein production from the structural genomics perspective: achievements and future needs

Cell-free expression—making a mark

Linking folding and binding

Many cellular proteins are intrinsically disordered and undergo folding, in whole or in part, upon binding to their physiological targets. The past few years have seen an exponential increase in papers describing characterization of intrinsically disordered proteins, both free and bound to targets. Although NMR spectroscopy remains the favored tool, a number of new biophysical techniques are proving exceptionally useful in defining the limits of the conformational ensembles. Advances have been…

Volume 19, Issue 1, 01 February 2009, Pp 31-38
Wright, P.E. | Dyson, H.J.

Function and structure of inherently disordered proteins

The application of bioinformatics methodologies to proteins inherently lacking 3D structure has brought increased attention to these macromolecules. Here topics concerning these proteins are discussed, including their prediction from amino acid sequence, their enrichment in eukaryotes compared to prokaryotes, their more rapid evolution compared to structured proteins, their organization into specific groups, their structural preferences, their half-lives in cells, their contributions to…

Volume 18, Issue 6, 01 December 2008, Pp 756-764
Dunker, A.K. | Silman, I. | Uversky, V.N. | Sussman, J.L.

Protein folding studied by single-molecule FRET

A complete understanding of a protein-folding mechanism requires description of the distribution of microscopic pathways that connect the folded and unfolded states. This distribution can, in principle, be described by computer simulations and theoretical models of protein folding, but is hidden in conventional experiments on large ensembles of molecules because only average properties are measured. A long-term goal of single-molecule fluorescence studies is to time-resolve the structural…

Volume 18, Issue 1, 01 February 2008, Pp 16-26
Schuler, B. | Eaton, W.A.

The structural biology of HIV assembly

HIV assembly and replication proceed through the formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is…

Volume 18, Issue 2, 01 April 2008, Pp 203-217
Ganser-Pornillos, B.K. | Yeager, M. | Sundquist, W.I.

Long-timescale molecular dynamics simulations of protein structure and function

Molecular dynamics simulations allow for atomic-level characterization of biomolecular processes such as the conformational transitions associated with protein function. The computational demands of such simulations, however, have historically prevented them from reaching the microsecond and greater timescales on which these events often occur. Recent advances in algorithms, software, and computer hardware have made microsecond-timescale simulations with tens of thousands of atoms practical,…

Volume 19, Issue 2, 01 April 2009, Pp 120-127
Klepeis, J.L. | Lindorff-Larsen, K. | Dror, R.O. | Shaw, D.E.

The structures of quadruplex nucleic acids and their drug complexes

Quadruplex nucleic acids are four-stranded structures formed from short tracts of G-rich sequence associating together. Their formation from eukaryotic telomeric DNA sequences is well established, at least in vitro, and has more recently been the focus of attention as novel anticancer targets since their formation inhibits the telomerase complex from maintaining telomere length in cancer cells. Structural studies have revealed a diversity of topologies for telomeric quadruplexes, which are…

Volume 19, Issue 3, 01 June 2009, Pp 239-250
Neidle, S.

Flexible ligand docking to multiple receptor conformations: a practical alternative

State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and…

Volume 18, Issue 2, 01 April 2008, Pp 178-184
Totrov, M. | Abagyan, R.

RNA recognition motifs: boring? Not quite

The RNA recognition motif (RRM) is one of the most abundant protein domains in eukaryotes. While the structure of this domain is well characterized by the packing of two α-helices on a four-stranded β-sheet, the mode of protein and RNA recognition by RRMs is not clear owing to the high variability of these interactions. Here we report recent structural data on RRM-RNA and RRM-protein interactions showing the ability of this domain to modulate its binding affinity and specificity using each of…

Volume 18, Issue 3, 01 June 2008, Pp 290-298
Cléry, A. | Blatter, M. | Allain, F.H.-T.

Progress and challenges in protein structure prediction

Depending on whether similar structures are found in the PDB library, the protein structure prediction can be categorized into template-based modeling and free modeling. Although threading is an efficient tool to detect the structural analogs, the advancements in methodology development have come to a steady state. Encouraging progress is observed in structure refinement which aims at drawing template structures closer to the native; this has been mainly driven by the use of multiple structure…

Volume 18, Issue 3, 01 June 2008, Pp 342-348
Zhang, Y.

Sialic acids as regulators of molecular and cellular interactions

The wide occurrence of sialic acids (Sia) in various chemical forms linked as monomers or polymers in an outstanding position in a multitude of complex carbohydrates of animals and microorganisms renders them as most versatile function modulators in cell biology and pathology. A survey is presented of recent advances in the study of the influences that Sias have as bulky hydrophilic and electronegatively charged monosaccharides on animal cells and on their interaction with microorganisms. Some…

Volume 19, Issue 5, 01 October 2009, Pp 507-514
Schauer, R.

Recent advances in implicit solvent-based methods for biomolecular simulations

Implicit solvent-based methods play an increasingly important role in molecular modeling of biomolecular structure and dynamics. Recent methodological developments have mainly focused on the extension of the generalized Born (GB) formalism for variable dielectric environments and accurate treatment of nonpolar solvation. Extensive efforts in parameterization of GB models and implicit solvent force fields have enabled ab initio simulation of protein folding to native or near-native structures.…

Volume 18, Issue 2, 01 April 2008, Pp 140-148
Chen, J. | Brooks III, C.L. | Khandogin, J.

Poly(dA:dT) tracts: major determinants of nucleosome organization

Homopolymeric stretches of deoxyadenosine nucleotides (A's) on one strand of double-stranded DNA, referred to as poly(dA:dT) tracts or A-tracts, are overabundant in eukaryotic genomes. They have unusual structural, dynamic, and mechanical properties, and may resist sharp bending. Such unusual material properties, together with their overabundance in eukaryotes, raised the possibility that poly(dA:dT) tracts might function in eukaryotes to influence the organization of nucleosomes at many…

Volume 19, Issue 1, 01 February 2009, Pp 65-71
Segal, E. | Widom, J.

Transition networks for modeling the kinetics of conformational change in macromolecules

The kinetics and thermodynamics of complex transitions in biomolecules can be modeled in terms of a network of transitions between the relevant conformational substates. Such a transition network, which overcomes the fundamental limitations of reaction-coordinate-based methods, can be constructed either based on the features of the energy landscape, or from molecular dynamics simulations. Energy-landscape-based networks are generated with the aid of automated path-optimization methods, and,…

Volume 18, Issue 2, 01 April 2008, Pp 154-162
Noé, F. | Fischer, S.

SF1 and SF2 helicases: Family matters

Helicases of the superfamily (SF) 1 and 2 are involved in virtually all aspects of RNA and DNA metabolism. SF1 and SF2 helicases share a catalytic core with high structural similarity, but different enzymes even within each SF perform a wide spectrum of distinct functions on diverse substrates. To rationalize similarities and differences between these helicases, we outline a classification based on protein families that are characterized by typical sequence, structural, and mechanistic…

Volume 20, Issue 3, 01 June 2010, Pp 313-324
Fairman-Williams, M.E. | Guenther, U.-P. | Jankowsky, E.

Membrane proteins: molecular dynamics simulations

Molecular dynamics simulations of membrane proteins are making rapid progress, because of new high-resolution structures, advances in computer hardware and atomistic simulation algorithms, and the recent introduction of coarse-grained models for membranes and proteins. In addition to several large ion channel simulations, recent studies have explored how individual amino acids interact with the bilayer or snorkel/anchor to the headgroup region, and it has been possible to calculate…

Volume 18, Issue 4, 01 August 2008, Pp 425-431
Lindahl, E. | Sansom, M.S.

Biophysical characterization of intrinsically disordered proteins

The challenges associated with the structural characterization of disordered proteins have resulted in the application of a host of biophysical methods to such systems. NMR spectroscopy is perhaps the most readily suited technique for providing high-resolution structural information on disordered protein states in solution. Optical methods, solid state NMR, ESR and X-ray scattering can also provide valuable information regarding the ensemble of conformations sampled by disordered states.…

Volume 19, Issue 1, 01 February 2009, Pp 23-30
Eliezer, D.

Coarse-grained models of protein folding: toy models or predictive tools?

Coarse-grained models are emerging as a practical alternative to all-atom simulations for the characterization of protein folding mechanisms over long time scales. While a decade ago minimalist toy models were mainly designed to test general hypotheses on the principles regulating protein folding, the latest coarse-grained models are increasingly realistic and can be used to characterize quantitatively the detailed folding mechanism of specific proteins. The ability of such models to reproduce…

Volume 18, Issue 1, 01 February 2008, Pp 10-15
Clementi, C.

RNA dynamics: it is about time

Many recently discovered RNA functions rely on highly complex multistep conformational transitions that occur in response to an array of cellular signals. These dynamics accompany and guide, for example, RNA cotranscriptional folding, ligand sensing and signaling, site-specific catalysis in ribozymes, and the hierarchically ordered assembly of ribonucleoproteins. RNA dynamics are encoded by both the inherent properties of RNA structure, spanning many motional modes with a large range of…

Volume 18, Issue 3, 01 June 2008, Pp 321-329
Al-Hashimi, H.M. | Walter, N.G.

Chaperone machines in action

How do chaperones operate in cells? For some major chaperones it is clear what they do, though mostly not how they do it. Hsp60, 70 and 100 families carry out folding, unfolding or disaggregation of proteins. Regarding mechanisms of action, we have the clearest picture of the ATP-driven mechanism of the bacterial Hsp60s, and structures of full-length Hsp70 and 90 family members are beginning to give insights into their allosteric mechanisms. Recent advances are giving an improved understanding…

Volume 18, Issue 1, 01 February 2008, Pp 35-42
Saibil, H.R.

Stability effects of mutations and protein evolvability

The past several years have seen novel insights at the interface of protein biophysics and evolution. The accepted paradigm that proteins can tolerate nearly any amino acid substitution has been replaced by the view that the deleterious effects of mutations, and especially their tendency to undermine the thermodynamic and kinetic stability of protein, is a major constraint on protein evolvability-the ability of proteins to acquire changes in sequence and function. We summarize recent findings…

Volume 19, Issue 5, 01 October 2009, Pp 596-604
Tokuriki, N. | Tawfik, D.S.

Type IV pili: paradoxes in form and function

Type IV pili are filaments on the surfaces of many Gram-negative bacteria that mediate an extraordinary array of functions, including adhesion, motility, microcolony formation and secretion of proteases and colonization factors. Their prominent display on the surfaces of many bacterial pathogens, their vital role in virulence, and their ability to elicit an immune response make Type IV pilus structures particularly relevant for study as targets for component vaccines and therapies. Structural…

Volume 18, Issue 2, 01 April 2008, Pp 267-277
Craig, L. | Li, J.

Histone chaperones in nucleosome eviction and histone exchange

The recent two years have led to the realization that histone chaperones contribute to the delicate balance between nucleosome assembly and re-assembly during transcription, and may in fact be involved as much in histone eviction as they are in chromatin assembly. Recent structural studies (in particular, the structure of an Asf1-H3/H4 complex) have suggested mechanisms by which this may be accomplished. The incorporation of various histone variants into nucleosomes has diverse effects on…

Volume 18, Issue 3, 01 June 2008, Pp 282-289
Park, Y.-J. | Luger, K.

Towards atomic resolution structural determination by single-particle cryo-electron microscopy

Recent advances in cryo-electron microscopy and single-particle reconstruction (collectively referred to as 'cryoEM') have made it possible to determine the three-dimensional (3D) structures of several macromolecular complexes at near-atomic resolution (∼3.8-4.5 Å). These achievements were accomplished by overcoming the challenges in sample handling, instrumentation, image processing, and model building. At near-atomic resolution, many detailed structural features can be resolved, such as the…

Volume 18, Issue 2, 01 April 2008, Pp 218-228
Zhou, Z.H.

Convergence and combination of methods in protein-protein docking

The analysis of results from Critical Assessment of Predicted Interactions (CAPRI), the first community-wide experiment devoted to protein docking, shows that all successful methods consist of multiple stages. The methods belong to three classes: global methods based on fast Fourier transforms (FFTs) or geometric matching, medium-range Monte Carlo methods, and the restraint-guided High Ambiguity Driven biomolecular DOCKing (HADDOCK) program. Although these classes of methods require very…

Volume 19, Issue 2, 01 April 2009, Pp 164-170
Vajda, S. | Kozakov, D.

Multiscale methods for macromolecular simulations

In this article we review the key modeling tools available for simulating biomolecular systems. We consider recent developments and representative applications of mixed quantum mechanics/molecular mechanics (QM/MM), elastic network models (ENMs), coarse-grained molecular dynamics, and grid-based tools for calculating interactions between essentially rigid protein assemblies. We consider how the different length scales can be coupled, both in a sequential fashion (e.g. a coarse-grained or grid…

Volume 18, Issue 5, 01 October 2008, Pp 630-640
Sherwood, P. | Brooks, B.R. | Sansom, M.S.

Single-molecule spectroscopy of protein folding dynamics—expanding scope and timescales

TAL effectors: function, structure, engineering and applications

Expression in Escherichia coli: becoming faster and more complex

Mass spectrometry supported determination of protein complex structure

To milliseconds and beyond: challenges in the simulation of protein folding

Molten globules, entropy-driven conformational change and protein folding

Crystal structure of the 80S yeast ribosome

Zinc finger proteins: new insights into structural and functional diversity

The dark energy of proteins comes to light: conformational entropy and its role in protein function revealed by NMR relaxation

Catechol oxidase — structure and activity