Why twenty amino acid residue types suffice(d) to support all living systems.

It is well known that proteins are built up from an alphabet of 20 different amino acid types. These suffice to enable the protein to fold into its operative form relevant to its required functional roles. For carrying out these allotted functions, there may in some cases be a need for post-translational modifications and it has been established that an additional three types of amino acid have at some point been recruited into this process.

A tensegrity model for hydrogen bond networks in proteins.

Hydrogen-bonding networks in proteins considered as structural tensile elements are in balance separately from any other stabilising interactions that may be in operation. The hydrogen bond arrangement in the network is reminiscent of tensegrity structures in architecture and sculpture. Tensegrity has been discussed before in cells and tissues and in proteins.

The fate of proteins in outer space.

It is well established that any properly conducted biophysical studies of proteins must take appropriate account of solvent. For water-soluble proteins it has been an article of faith that water is largely responsible for stabilizing the fold, a notion that has recently come under increasing scrutiny. Further, there are some instances when proteins are studied experimentally in the absence of solvent, as in matrix-assisted laser desorption/ionization or electrospray mass spectrometry, for example, or in organic solvents for protein engineering purposes.

Melody discrimination and protein fold classification.

One of the greatest challenges in theoretical biophysics and bioinformatics is the identification of protein folds from sequence data. This can be regarded as a pattern recognition problem. In this paper we report the use of a melody generation software where the inputs are derived from calculations of evolutionary information, secondary structure, flexibility, hydropathy and solvent accessibility from multiple sequence alignment data.

Comparison of Algorithms for Prediction of Protein Structural Features from Evolutionary Data.

Proteins have many functions and predicting these is still one of the major challenges in theoretical biophysics and bioinformatics. Foremost amongst these functions is the need to fold correctly thereby allowing the other genetically dictated tasks that the protein has to carry out to proceed efficiently. In this work, some earlier algorithms for predicting protein domain folds are revisited and they are compared with more recently developed methods.

The dipeptide conformations of all twenty amino acid types in the context of biosynthesis.

There have been many studies of dipeptide structure at a high level of accuracy using quantum chemical methods. Such calculations are resource-consuming (in terms of memory, CPU and other computational imperatives) which is the reason why most previous studies were restricted to the two simplest amino-acid residue types, glycine and alanine. We improve on this by extending the scope of residue types to include all 20 naturally occurring residue types.

Prediction of protein structural features from sequence data based on Shannon entropy and Kolmogorov complexity.

While the genome for a given organism stores the information necessary for the organism to function and flourish it is the proteins that are encoded by the genome that perhaps more than anything else characterize the phenotype for that organism. It is therefore not surprising that one of the many approaches to understanding and predicting protein folding and properties has come from genomics and more specifically from multiple sequence alignments. In this work I explore ways in which data derived from sequence alignment data can be used to investigate in a predictive way three different aspects of protein structure: secondary structures, inter-residue contacts and the dynamics of switching between different states of the protein.

The preferred conformation of dipeptides in the context of biosynthesis.

Globular proteins are folded polypeptide structures comprising stretches of secondary structures (helical (α- or 310 helix type), polyproline helix or β-strands) interspersed by regions of less well-ordered structure ("random coil"). Protein fold prediction is a very active field impacting inte alia on protein engineering and misfolding studies. Apart from the many studies of protein refolding from the denatured state, there has been considerable interest in studying the initial formation of peptides during biosynthesis, when there are at the outset only a few residues in the emerging polypeptide.

Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery.

The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors.

Protein folding: a problem with multiple solutions.

There is continued interest in predicting the structure of proteins either at the simplest level of identifying their fold class or persevering all the way to an atomic resolution structure. Protein folding methods have become very sophisticated and many successes have been recorded with claims to have solved the native structure of the protein. But for any given protein, there may be more than one solution.

Accelerated simulation of unfolding and refolding of a large single chain globular protein.

We have developed novel strategies for contracting simulation times in protein dynamics that enable us to study a complex protein with molecular weight in excess of 34 kDa. Starting from a crystal structure, we produce unfolded and then refolded states for the protein. We then compare these quantitatively using both established and new metrics for protein structure and quality checking.

Inactivation and reactivation of ribonuclease A studied by computer simulation.

The year 2011 marked the half-centenary of the publication of what came to be known as the Anfinsen postulate, that the tertiary structure of a folded protein is prescribed fully by the sequence of its constituent amino acid residues. This postulate has become established as a credo, and, indeed, no contradictions seem to have been found to date. However, the experiments that led to this postulate were conducted on only a single protein, bovine ribonuclease A (RNAse).

G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment.

Our previously derived models of the active state of the β2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). These molecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The β2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures.

On dating stages in prebiotic chemical evolution.

The notion that RNA must have had a unique and decisive role in the development of life needs hardly be questioned. However, the chemical complexity and other properties of RNA, such as high solubility in water and vulnerability to degradation, make it improbable that RNA could have had an early presence in the development of life on Earth or on any comparable telluric planet. Rather, the task of origin of life research must surely be to identify those chemical processes which could have taken place on Earth that could accumulate the complexity and rich molecular information content needed to sustain primitive life, and ultimately give rise to RNA.

Drug design for ever, from hype to hope.

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly.

Membrane-spanning peptides and the origin of life.

An explanation is given as to why membrane-spanning peptides must have been the first "information-rich" molecules in the development of life. These peptides are stabilised in a lipid bilayer membrane environment and they are preferentially made from the simplest, and likewise oldest, of the amino acids that survive today. Transmembrane peptides can exercise functions that are essential for biological systems such as signal transduction and material transport across membranes.

A pan-European survey of antimicrobial susceptibility towards human-use antimicrobial drugs among zoonotic and commensal enteric bacteria isolated from healthy food-producing animals.

Objectives: The aim of the study was to study antimicrobial susceptibility in Escherichia coli, Salmonella, Campylobacter and Enterococcus recovered from chickens, pigs and cattle using uniform methodology.

Methods: Intestinal samples were taken at slaughter in five EU countries per host and bacteria isolated in national laboratories. MICs were determined in a central laboratory of key antimicrobials used in human medicine.

Privileged structures in GPCRs.

Certain kinds of ligand substructures recur frequently in pharmacologically successful synthetic compounds. For this reason they are called privileged structures. In seeking an explanation for this phenomenon, it is observed that the privileged structure represents a generic substructure that matches commonly recurring conserved structural motifs in the target proteins, which may otherwise be quite diverse in sequence and function.

Modeling GPCRs.

Many GPCR models have been built over the years for many different purposes, of which drug-design undoubtedly has been the most frequent one. The release of the structure of bovine rhodopsin in August 2000 enabled us to analyze models built before that period to learn things for the models we build today. We conclude that the GPCR modeling field is riddled with "common knowledge".

Residues from transmembrane helices 3 and 5 participate in leukotriene B4 binding to BLT1.

Leukotrienes are inflammatory mediators that bind to seven transmembrane, G-protein-coupled receptors (GPCRs). Here we examine residues from transmembrane helices 3 and 5 of the leukotriene B4 (LTB4) receptor BLT1 to elucidate how these residues are involved in ligand binding. We have selected these residues on the basis of (1) amino acid sequence analysis, (2) receptor binding and activation studies with a variety of leukotriene-like ligands and recombinant BLT1 receptors, (3) previously published recombinant BLT1 mutants, and (4) a computed model of the active structure of the BLT1 receptor.

The susceptibility to growth-promoting antibiotics of Enterococcus faecium isolates from pigs and chickens in Europe.

Objectives: To establish the susceptibility of Enterococcus faecium isolates from pigs and chickens to antimicrobial growth promoters that either were or had been in use in the European Union.

Methods: Samples were taken at abattoirs in two successive years (mid-1998-mid-1999, year 1; mid-1999-mid-2000, year 2) from chickens (France, The Netherlands, Sweden, UK) and pigs (Denmark, The Netherlands, Spain, Sweden). E.