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Seddon G.,Adelard Institute | Lounnas V.,Radboud University Nijmegen | McGuire R.,Bioaxis Research | Van Den Bergh T.,Bio Prodict | And 3 more authors.
Journal of Computer-Aided Molecular Design | Year: 2012

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. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data. © 2012 The Author(s).

Seddon G.M.,Adelard Institute | Bywater R.P.,Manchester College
International Journal of Astrobiology | Year: 2015

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. Apart from these considerations, there is considerable speculation as to whether there is life on planets other than Earth, where conditions including the presence of water (both in liquid or vapour form and indeed ice), temperature and pressure may be vastly different from those prevailing on Earth. Mars, for example, has only 0.6% of Earth's mean atmospheric pressure which presents profound problems to protein structures, as this paper and a large corpus of experimental work demonstrate. Similar objections will most likely apply in the case of most exoplanets and other bodies such as comets whose chemistry and climate are still largely unknown. This poses the question, how do proteins survive in these different environments? In order to cast some light on these issues we have conducted a series of molecular dynamics simulations on protein dehydration under a variety of conditions. We find that, while proteins undergoing dehydration can retain their integrity for a short duration they ultimately become disordered, and we further show that the disordering can be retarded if superficial water is kept in place on the surface. These findings are compared with other published results on protein solvation in an astrobiological and astrochemical setting. Inter alia, our results suggest that there are limits as to what to expect in terms of the existence of possible extraterrestrial forms as well to what can be achieved in experimental investigations on living systems despatched from Earth. This finding may appear to undermine currently held hopes that life will be found on nearby planets, but it is important to be aware that the presence of ice and water are by themselves not sufficient; there has to be an atmosphere which includes water vapour at a sufficiently high partial pressure for proteins to be active. A possible scenario in which there has been a history of adequate water vapour pressure which allowed organisms to prepare for a future desiccated state by forming suitable protective capsules cannot of course be ruled out. Copyright © Cambridge University Press 2015

Seddon G.M.,Adelard Institute | Bywater R.P.,Adelard Institute | Bywater R.P.,Magdalen College
Open Biology | Year: 2012

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. These include use of the programs CONCOORD and DARVOLS. Simulation of protein-folded structure well beyond the molten globule state and then recovery back to the folded state is itself new, and our results throw new light on the protein-folding process. We accomplish this using a novel cooling protocol developed for this work. © 2012 The Authors.

Seddon G.M.,Adelard Institute | Bywater R.P.,Adelard Institute | Bywater R.P.,Magdalen College
Open Biology | Year: 2012

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). We conduct molecular dynamics (MD) simulations on this protein with the aim of mimicking this experiment as well as making the methodology available for use with basically any protein. There have been many attempts to model denaturation and refolding processes of globular proteins in silico using MD, but only a few examples where disulphide-bond containing proteins were studied. We took the view that if the reductive deactivation and oxidative reactivation processes of RNAse could be modelled in silico, this would provide valuable insights into the workings of the classical Anfinsen experiment. © 2012 The Authors.

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