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Sjostrand J.,University of Stockholm | Sennblad B.,University of Stockholm | Sennblad B.,Karolinska Institutet | Arvestad L.,University of Stockholm | And 3 more authors.
Bioinformatics | Year: 2012

PrIME-DLRS (or colloquially: 'Delirious') is a phylogenetic software tool to simultaneously infer and reconcile a gene tree given a species tree. It accounts for duplication and loss events, a relaxed molecular clock and is intended for the study of homologous gene families, for example in a comparative genomics setting involving multiple species. PrIME-DLRS uses a Bayesian MCMC framework, where the input is a known species tree with divergence times and a multiple sequence alignment, and the output is a posterior distribution over gene trees and model parameters. © 2012 The Author.

Schlatter P.,KTH Royal Institute of Technology | Schlatter P.,Swedish ience Research Center | Li Q.,KTH Royal Institute of Technology | Li Q.,Swedish ience Research Center | And 4 more authors.
European Journal of Mechanics, B/Fluids | Year: 2014

A recent database from direct numerical simulation (DNS) of a turbulent boundary layer up to Reθ=4300 (Schlatter and Örlü, 2010) is analysed to extract the dominant flow structures in the near-wall region. In particular, the question of whether hairpin vortices are significant features of near-wall turbulence is addressed. A number of different methods based on the λ2 criterion (Jeong and Hussain, 1995) is used to extract turbulent coherent structures: three-dimensional flow visualisation with quantitative estimates of hairpin population, conditional averaging and planar hairpin vortex signatures (HVS). First, visualisations show that during the initial phase of laminar-turbulent transition induced via tripping, hairpin vortices evolving from transitional Λ vortices are numerous and can be considered as the dominant structure of the immediate post-transition stage of the boundary layer. This is in agreement with previous experiments and low-Reynolds-number simulations such as Wu & Moin (2009). When the Reynolds number is increased, the fraction of hairpin vortices decreases to less than 2% for Reθ>4000. Second, conditional ensemble averages (Jeong et al., 1997) find hairpins close to the wall at low Reynolds number, while at a sufficient distance downstream from transition, the flow close to the wall is dominated by single quasi-streamwise vortices; even quantitatively, no major differences between boundary layer and channel can be detected. Moreover, three-dimensional visualisations of the neighbourhood of regions of strong swirling motion in planar cuts through the layer (the HVS) do not reveal hairpin vortices, thereby impairing statistical evidences based on HVS. The present results thus clearly confirm that transitional hairpin vortices do not persist in fully developed turbulent boundary layers, and that their dominant appearance as instantaneous flow structures in the outer boundary-layer region is very unlikely. © 2014 Elsevier Masson SAS. All rights reserved.

Andersson M.,University of California at Irvine | Andersson M.,Swedish ience Research Center | Andersson M.,Paul Scherrer Institute | Mattle D.,University of Aarhus | And 9 more authors.
Nature Structural and Molecular Biology | Year: 2014

Heavy metals in cells are typically regulated by P IB-type ATPases. The first structure of the class, a Cu +-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu +-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu +-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized P II-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens. © 2014 Nature America, Inc. All rights reserved.

Rodriguez D.,University of Stockholm | Rodriguez D.,Swedish ience Research Center | Gao Z.-G.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Moss S.M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | And 3 more authors.
Journal of Chemical Information and Modeling | Year: 2015

Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A2A adenosine receptor (A2AAR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A2AAR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A2AAR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A2AAR agonists and general strategies for structure-based drug discovery. © 2015 American Chemical Society.

Plotnikov N.V.,University of Southern California | Kamerlin S.C.L.,University of Stockholm | Kamerlin S.C.L.,Stockholm Center for Biomembrane Research | Kamerlin S.C.L.,Swedish ience Research Center | Warshel A.,University of Southern California
Journal of Physical Chemistry B | Year: 2011

Recent years have seen tremendous effort in the development of approaches with which to obtain quantum mechanics/molecular mechanics (QM/MM) free energies for reactions in the condensed phase. Nevertheless, there remain significant challenges to address, particularly, the high computational cost involved in performing proper configurational sampling and, in particular, in obtaining ab initio QM/MM (QM(ai)/MM) free-energy surfaces. One increasingly popular approach that seems to offer an ideal way to progress in this direction is the elegant metadynamics (MTD) approach. However, in the current work, we point out the subtle efficiency problems associated with this approach and illustrate that we have at hand what is arguably a more powerful approach. More specifically, we demonstrate the effectiveness of an updated version of our original idea of using a classical reference potential for QM(ai)/MM calculations [J. Phys. Chem. 1995, 99, 17516)], which we refer to as paradynamics (PD). This approach is based on the use of an empirical valence bond (EVB) reference potential, which is already similar to the real ab initio potential. The reference potential is fitted to the ab initio potential by an iterative and, to a great degree, automated refinement procedure. The corresponding free-energy profile is then constructed using the refined EVB potential, and the linear response approximation (LRA) is used to evaluate the QM(ai)/MM activation free-energy barrier. The automated refinement of the EVB surface (and thus the reduction of the difference between the reference and ab initio potentials) is a key factor in accelerating the convergence of the LRA approach. We apply our PD approach to a test reaction, namely, the SN2 reaction between a chloride ion and methyl chloride, and demonstrate that, at present, this approach is far more powerful and cost-effective than the metadynamics approach (at least in its current implementation). We also discuss the general features of the PD approach in terms of its ability to explore complex systems and clarify that it is not a specialized approach limited to only accelerating QM(ai)/MM calculations with proper sampling, but rather can be used in a wide variety of applications. In fact, we point out that the use of a reference (CG) potential coupled with its PD refinement, as well as our renormalization approach, provides very general and powerful strategies that can be used very effectively to explore any property that has been studied by the MTD approach. © 2011 American Chemical Society.

Schreiber F.,Stockholm Bioinformatics Center | Schreiber F.,University of Stockholm | Sonnhammer E.L.L.,Stockholm Bioinformatics Center | Sonnhammer E.L.L.,University of Stockholm | Sonnhammer E.L.L.,Swedish ience Research Center
Journal of Molecular Biology | Year: 2013

An accurate inference of orthologs is essential in many research fields such as comparative genomics, molecular evolution, and genome annotation. Existing methods for genome-scale orthology inference are mostly based on all-versus-all similarity searches that scale quadratically with the number of species. This limits their application to the increasing number of available large-scale datasets. Here, we present Hieranoid, a new orthology inference method using a hierarchical approach. Hieranoid performs pairwise orthology analysis using InParanoid at each node in a guide tree as it progresses from its leaves to the root. This concept reduces the total runtime complexity from a quadratic to a linear function of the number of species. The tree hierarchy provides a natural structure in multi-species ortholog groups, and the aggregation of multiple sequences allows for multiple alignment similarity searching techniques, which can yield more accurate ortholog groups. Using the recently published orthobench benchmark, Hieranoid showed the overall best performance. Our progressive approach presents a new way to infer orthologs that combines efficient graph-based methodology with aspects of compute-intensive tree-based methods. The linear scaling with the number of species is a major advantage for large-scale applications and makes Hieranoid well suited to cope with vast amounts of sequenced genomes in the future. Hieranoid is an open source and can be downloaded at © 2013 Elsevier Ltd. All rights reserved.

Rodriguez D.,University of Stockholm | Rodriguez D.,Swedish ience Research Center | Ranganathan A.,University of Stockholm | Ranganathan A.,Swedish ience Research Center | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2014

The recent increase in the number of atomic-resolution structures of G protein-coupled receptors (GPCRs) has contributed to a deeper understanding of ligand binding to several important drug targets. However, reliable modeling of GPCR-ligand complexes for the vast majority of receptors with unknown structure remains to be one of the most challenging goals for computer-aided drug design. The GPCR Dock 2013 assessment, in which researchers were challenged to predict the crystallographic structures of serotonin 5-HT1B and 5-HT 2B receptors bound to ergotamine, provided an excellent opportunity to benchmark the current state of this field. Our contributions to GPCR Dock 2013 accurately predicted the binding mode of ergotamine with RMSDs below 1.8 Å for both receptors, which included the best submissions for the 5-HT1B complex. Our models also had the most accurate description of the binding sites and receptor-ligand contacts. These results were obtained using a ligand-guided homology modeling approach, which combines extensive molecular docking screening with incorporation of information from multiple crystal structures and experimentally derived restraints. In this work, we retrospectively analyzed thousands of structures that were generated during the assessment to evaluate our modeling strategies. Major contributors to accuracy were found to be improved modeling of extracellular loop two in combination with the use of molecular docking to optimize the binding site for ligand recognition. Our results suggest that modeling of GPCR-drug complexes has reached a level of accuracy at which structure-based drug design could be applied to a large number of pharmaceutically relevant targets. © 2014 American Chemical Society.

Rodriguez D.,University of Stockholm | Rodriguez D.,Swedish ience Research Center | Brea J.,University of Santiago de Compostela | Loza M.I.,University of Santiago de Compostela | And 2 more authors.
Structure | Year: 2014

Summary The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT 1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. © 2014 Elsevier Ltd.

Kamerlin S.C.L.,University of Stockholm | Kamerlin S.C.L.,Swedish ience Research Center | Warshel A.,University of Southern California
Physical Chemistry Chemical Physics | Year: 2011

Recent years have witnessed a tremendous explosion in computational power, which in turn has resulted in great progress in the complexity of the biological and chemical problems that can be addressed by means of all-atom simulations. Despite this, however, our computational time is not infinite, and in fact many of the key problems of the field were resolved long before the existence of the current levels of computational power. This review will start by presenting a brief historical overview of the use of multiscale simulations in biology, and then present some key developments in the field, highlighting several cases where the use of a physically sound simplification is clearly superior to a brute-force approach. Finally, some potential future directions will be discussed. © the Owner Societies 2011.

Light S.,University of Stockholm | Sagit R.,University of Stockholm | Ekman D.,Karolinska Institutet | Elofsson A.,University of Stockholm | Elofsson A.,Swedish ience Research Center
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2013

Proteins evolve through point mutations as well as by insertions and deletions (indels). During the last decade it has become apparent that protein regions that do not fold into three-dimensional structures, i.e. intrinsically disordered regions, are quite common. Here, we have studied the relationship between protein disorder and indels using HMM-HMM pairwise alignments in two sets of orthologous eukaryotic protein pairs. First, we show that disordered residues are much more frequent among indel residues than among aligned residues and, also are more prevalent among indels than in coils. Second, we observed that disordered residues are particularly common in longer indels. Disordered indels of short-to-medium size are prevalent in the non-terminal regions of proteins while the longest indels, ordered and disordered alike, occur toward the termini of the proteins where new structural units are comparatively well tolerated. Finally, while disordered regions often evolve faster than ordered regions and disorder is common in indels, there are some previously recognized protein families where the disordered region is more conserved than the ordered region. We find that these rare proteins are often involved in information processes, such as RNA processing and translation. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly. © 2013 Elsevier B.V.

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