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rstoolbox: management and analysis of computationally designed structural ensembles [article]

Jaume Bonet, Zander Harteveld, Fabian Sesterhenn, Andreas Scheck, Bruno E. Correia
2018 bioRxiv   pre-print
AbstractMotivationComputational protein design (CPD) calculations rely on the generation of large amounts of data on the search for the best sequences. As such, CPD workflows generally include the batch generation of designed decoys (sampling) followed by ranking and filtering stages to select those with optimal metrics (scoring). Due to these factors, the proper analysis of the decoy population is a key element for the effective selection of designs for experimental validation.ResultsHere, we
more » ... resent a set of tools for the analysis of protein design ensembles. The tool is oriented towards protein designers with basic coding training aiming to process efficiently their decoy sets as well as for protocol developers interested in benchmarking their new approaches. Although initially devised to process Rosetta design outputs, the library is extendable to other design tools.Availability and Implementationrstoolbox is implemented for python2.7 and 3.5+. Code is freely available at under the MIT license. Full documentation and examples can be found at
doi:10.1101/428045 fatcat:dkyewymzh5fxzljrxixfi7i53m

RosettaSurf - a surface-centric computational design approach [article]

Andreas Scheck, Stephane Rosset, Michael Defferrard, Andreas Loukas, Jaume Bonet, Pierre Vandergheynst, Bruno E. Correia
2021 bioRxiv   pre-print
Andreas Loukas was supported by the Swiss National Science 641 Foundation project "Deep Learning for Graph-Structured Data" (grant number PZ00P2 179981). 642 Jaume Bonet was funded by the EPFL Fellows  ... 
doi:10.1101/2021.06.16.448645 fatcat:gv5e4hmjf5fbzpqonym3d5jupy

Multivalent antibodies: when design surpasses evolution

Ángel M. Cuesta, Noelia Sainz-Pastor, Jaume Bonet, Baldomero Oliva, Luis Álvarez-Vallina
2010 Trends in Biotechnology  
Evolutionary pressure has selected antibodies as key immune molecules acting against foreign pathogens. The development of monoclonal antibody technology has allowed their widespread use in research, real-time diagnosis and treatment of multiple diseases, including cancer. However, compared with hematologic malignancies, solid tumors have often proven to be relatively resistant to antibody-based therapies. In an attempt to improve the tumor-targeting efficacy of antibodies, new formats with
more » ... fied, multivalent properties have been generated. Initially, these formats imitated the structure of native IgG, creating mostly monospecific, bivalent antibodies. Recently, novel trivalent antibodies have been developed to maximize tumor targeting capabilities through enhanced biodistribution and functional affinity. We review recent advances in the engineering of multivalent antibodies and further discuss their promise as agents for in vivo diagnostics and therapy.
doi:10.1016/j.tibtech.2010.03.007 pmid:20447706 fatcat:y5fum7gptbbwfolkke6djq6mzi

Mutational hotspot in the SARS-CoV-2 Spike protein N-terminal domain conferring immune escape potential [article]

Slawomir Kubik, Nils Arrigo, Jaume Bonet, Zhenyu Xu
2021 bioRxiv   pre-print
ABSTRACTGlobal efforts are being taken to monitor the evolution of SARS-CoV-2, aiming at early identification of mutations with the potential of increasing viral infectivity or virulence. We report a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. We investigate the impact these mutations might
more » ... on the evasion of neutralizing antibodies. Finally, we uncover that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path on which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape.
doi:10.1101/2021.05.28.446137 fatcat:stkbb6xl75gbvc5vtvcgd22kcm

RADI (Reduced Alphabet Direct Information): Improving execution time for direct-coupling analysis [article]

Bernat Anton, Mireia Besalu, Oriol Fornes, Jaume Bonet, Gemma De las Cuevas, Narcis Fernandez-Fuentes, Baldomero Oliva
2018 bioRxiv   pre-print
Motivation: Direct-coupling analysis (DCA) for studying the coevolution of residues in proteins has been widely used to predict the three-dimensional structure of a protein from its sequence. Current algorithms for DCA, although efficient, have a high computational cost of determining Direct Information (DI) values for large proteins or domains. In this paper, we present RADI (Reduced Alphabet Direct Information), a variation of the original DCA algorithm that simplifies the computation of DI
more » ... lues by grouping physicochemically equivalent residues. Results: We have compared the first top ranking 40 pairs of DI values and their closest paired contact in 3D. The ranking is also compared with results obtained using a similar but faster approach based on Mutual Information (MI). When we simplify the number of symbols used to describe a protein sequence to 9, RADI achieves similar results as the original DCA (i.e. with the classical alphabet of 21 symbols), while reducing the computation time around 30-fold on large proteins (with length around 1000 residues) and with higher accuracy than predictions based on MI. Interestingly, the simplification produced by grouping amino acids into only two groups (polar and non-polar) is still representative of the physicochemical nature that characterizes the protein structure, having a relevant and useful predictive value, while the computation time is reduced between 100 and 2500-fold. Availability: RADI is available at Supplementary information: Supplementary data is available in the git repository.
doi:10.1101/406603 fatcat:4tbcfrxuivgspaybr5jstxm2eq

RosettaSurf—A surface-centric computational design approach

Andreas Scheck, Stéphane Rosset, Michaël Defferrard, Andreas Loukas, Jaume Bonet, Pierre Vandergheynst, Bruno E. Correia, Joanna Slusky
2022 PLoS Computational Biology  
Proteins are typically represented by discrete atomic coordinates providing an accessible framework to describe different conformations. However, in some fields proteins are more accurately represented as near-continuous surfaces, as these are imprinted with geometric (shape) and chemical (electrostatics) features of the underlying protein structure. Protein surfaces are dependent on their chemical composition and, ultimately determine protein function, acting as the interface that engages in
more » ... teractions with other molecules. In the past, such representations were utilized to compare protein structures on global and local scales and have shed light on functional properties of proteins. Here we describe RosettaSurf, a surface-centric computational design protocol, that focuses on the molecular surface shape and electrostatic properties as means for protein engineering, offering a unique approach for the design of proteins and their functions. The RosettaSurf protocol combines the explicit optimization of molecular surface features with a global scoring function during the sequence design process, diverging from the typical design approaches that rely solely on an energy scoring function. With this computational approach, we attempt to address a fundamental problem in protein design related to the design of functional sites in proteins, even when structurally similar templates are absent in the characterized structural repertoire. Surface-centric design exploits the premise that molecular surfaces are, to a certain extent, independent of the underlying sequence and backbone configuration, meaning that different sequences in different proteins may present similar surfaces. We benchmarked RosettaSurf on various sequence recovery datasets and showcased its design capabilities by generating epitope mimics that were biochemically validated. Overall, our results indicate that the explicit optimization of surface features may lead to new routes for the design of functional proteins.
doi:10.1371/journal.pcbi.1009178 pmid:35294435 pmcid:PMC9015148 fatcat:y44hufraovggrdqind255pbcru

ArchDB 2014: structural classification of loops in proteins

Jaume Bonet, Joan Planas-Iglesias, Javier Garcia-Garcia, Manuel A. Marín-López, Narcis Fernandez-Fuentes, Baldo Oliva
2013 Nucleic Acids Research  
The function of a protein is determined by its threedimensional structure, which is formed by regular (i.e. b-strands and a-helices) and non-periodic structural units such as loops. Compared to regular structural elements, non-periodic, non-repetitive conformational units enclose a much higher degree of variability-raising difficulties in the identification of regularities, and yet represent an important part of the structure of a protein. Indeed, loops often play a pivotal role in the function
more » ... of a protein and different aspects of protein folding and dynamics. Therefore, the structural classification of protein loops is an important subject with clear applications in homology modelling, protein structure prediction, protein design (e.g. enzyme design and catalytic loops) and function prediction. ArchDB, the database presented here (freely available at http://, represents such a resource and has been an important asset for the scientific community throughout the years. In this article, we present a completely reworked and updated version of ArchDB. The new version of ArchDB features a novel, fast and user-friendly web-based interface, and a novel graph-based, computationally efficient, clustering algorithm. The current version of ArchDB classifies 149,134 loops in 5739 classes and 9608 subclasses.
doi:10.1093/nar/gkt1189 pmid:24265221 pmcid:PMC3964960 fatcat:lylrty6wlbdv5hvwltkvne355a

Selection in the Introgressed Regions of the Chimpanzee Genome

Jessica Nye, Hafid Laayouni, Martin Kuhlwilm, Mayukh Mondal, Tomas Marques-Bonet, Jaume Bertranpetit
2018 Genome Biology and Evolution  
During the demographic history of the Pan clade, there has been gene-flow between species, likely >200,000 years ago. Bonobo haplotypes in three subspecies of chimpanzee have been identified to be segregating in modern-day chimpanzee populations, suggesting that these haplotypes, with increased differentiation, may be a target of natural selection. Here, we investigate signatures of adaptive introgression within the bonobo-like haplotypes in chimpanzees using site frequency spectrum-based
more » ... We find evidence for subspecies-specific adaptations in introgressed regions involved with male reproduction in central chimpanzees, the immune system in eastern chimpanzees, female reproduction and the nervous system in Nigeria-Cameroon chimpanzees. Furthermore, our results indicate signatures of balancing selection in some of the putatively introgressed regions. This might be the product of long-term balancing selection resulting in a similar genomic signature as introgression, or possibly balancing selection acting on alleles reintroduced through gene flow.
doi:10.1093/gbe/evy077 pmid:29635458 pmcid:PMC5905441 fatcat:mfpivtmairhvjk7bnyfwouwmfm

Characterization of Protein Hubs by Inferring Interacting Motifs from Protein Interactions

Ramon Aragues, Andrej Sali, Jaume Bonet, Marc Marti-Renom, Baldomero Oliva
2005 PLoS Computational Biology  
Citation: Aragues R, Sali A, Bonet J, Marti-Renom MA, Oliva B (2007) Characterization of protein hubs by inferring interacting motifs from protein interactions. PLoS Comput Biol 3(9): e178.  ... 
doi:10.1371/journal.pcbi.0030178.eor fatcat:62tadnzqebalzk3qgzjzglidxy

Characterization of Protein Hubs by Inferring Interacting Motifs from Protein Interactions

Ramon Aragues, Andrej Sali, Jaume Bonet, Marc A. Marti-Renom, Baldo Oliva
2007 PLoS Computational Biology  
Citation: Aragues R, Sali A, Bonet J, Marti-Renom MA, Oliva B (2007) Characterization of protein hubs by inferring interacting motifs from protein interactions. PLoS Comput Biol 3(9): e178.  ... 
doi:10.1371/journal.pcbi.0030178 pmid:17941705 pmcid:PMC1976338 fatcat:ojiupuzny5dcdnyj2ebt5vudde

Mutational Hotspot in the SARS-CoV-2 Spike Protein N-Terminal Domain Conferring Immune Escape Potential

Slawomir Kubik, Nils Arrigo, Jaume Bonet, Zhenyu Xu
2021 Viruses  
Global efforts are being made to monitor the evolution of SARS-CoV-2, aiming for early identification of genotypes providing increased infectivity or virulence. However, viral lineage-focused tracking might fail in early detection of advantageous mutations emerging independently across phylogenies. Here, the emergence patterns of Spike mutations were investigated in sequences deposited in local and global databases to identify mutational hotspots across phylogenies and we evaluated their impact
more » ... on SARS-CoV-2 evolution. We found a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. These mutations might have an impact on the evasion of neutralizing antibodies. Finally, we found that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path in which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape. We conclude that adaptive mutations, frequently present outside of the receptor-binding domain, can emerge in virtually any SARS-CoV-2 lineage and at any geographical location. Therefore, surveillance should not be restricted to monitoring defined lineages alone.
doi:10.3390/v13112114 pmid:34834921 pmcid:PMC8618472 fatcat:z4rijhozknblnbr65lmvwjja4m

Prediction of a new class of RNA recognition motif

Núria Cerdà-Costa, Jaume Bonet, M. Rosario Fernández, Francesc X. Avilés, Baldomero Oliva, Sandra Villegas
2010 Journal of Molecular Modeling  
The observation that activation domains (AD) of procarboxypeptidases are rather long, compared to pro-regions of other zymogens, points out the possibility that they could play additional roles apart from precluding enzymatic activity within the proenzyme and helping in its folding process. In the present work, we have compared the overall pro-domain tertiary structure with several proteins belonging to the same fold in SCOP by using structure and sequence comparisons. The best score has been
more » ... tained between the activation domain of the human procarboxypeptidase A4 (ADA4h) and the human U1A protein from the U1 snRNP. Structural alignment has revealed the existence of RNP1-and RNP2-related sequences in ADA4h. After modeling ADA4h on U1A, the new structure was used to extract a new sequence pattern characteristic for important residues at key positions. The new sequence pattern allowed scanning protein sequences to predict the RNA-binding function for 32 sequences undetected by PFAM. Unspecific RNA EMSA experimentally supported the prediction that ADA4h binds an RNA motif similar to the U1A binding-motif of stem-loop II of U1 small nuclear RNA. The experiments carried out with ADA4h in the present work Manuscript Click here to download Manuscript: JMMO1391R2_final.doc 2 suggest the sharing of a common ancestor with other RRMs. However, the fact that key residues preventing activity within the proenzyme are also key residues for RNA binding might induce the activation domains of procarboxypeptidases to evolve from the canonical RNP1 and 2 sequences.
doi:10.1007/s00894-010-0888-0 pmid:21082207 fatcat:n5duqjf3cvfk5fxdpoqcuiyp64

β-Carotene conversion products and their effects on adipose tissue

Franck Tourniaire, Erwan Gouranton, Johannes von Lintig, Jaap Keijer, M. Luisa Bonet, Jaume Amengual, Georg Lietz, Jean-François Landrier
2009 Genes & Nutrition  
Recent epidemiological data suggest that b-carotene may be protective against metabolic diseases in which adipose tissue plays a key role. Adipose tissue constitutes the major b-carotene storage tissue and its functions have been shown to be modulated in response to b-carotene breakdown products, especially retinal produced after cleavage by b-carotene 15,15 0 -monooxygenase (BCMO1), and retinoic acid arising from oxidation of retinal. However, the possibility exists that b-carotene in its
more » ... t form can also affect adipocyte function. Development of a knock out model and identification of a loss-offunction mutation have pointed out BCMO1 as being probably the sole enzyme responsible for provitamin A conversion into retinal in mammals. The utilisation of BCMO1 -/mice should provide insights on b-carotene effect on its own in the future. In humans, intervention studies have highlighted the huge interindividual variation of b-carotene conversion efficiency, possibly due to genetic polymorphisms, which might impact on response to b-carotene. This brief review discusses the processes involved in b-carotene conversion and the effect of cleavage products on body fat and adipose tissue function.
doi:10.1007/s12263-009-0128-3 pmid:19557453 pmcid:PMC2745744 fatcat:sp2ofpk3v5cvbinxxhxc2mcd3u

Increasing Dietary Lysine Impacts Differently Growth Performance of Growing Pigs Sorted by Body Weight

Pau Aymerich, Carme Soldevila, Jordi Bonet, Josep Gasa, Jaume Coma, David Solà-Oriol
2020 Animals  
An experiment was conducted analyzing whether growing pigs classified in different initial body weight categories (BWCAT) have a different response to increasing standardized ileal digestible lysine to net energy ratio (SID Lys:NE), to assess whether light pigs might benefit from being differentially fed. A total of 1170 pigs in pens of 13 were individually weighed, classified in 3 BWCAT (Lp: 32.1 ± 2.8 kg, Mp: 27.5 ± 2.3 kg, and Sp: 23.4 ± 2.9 kg), and afterwards pens were randomly allocated
more » ... 5 dietary SID Lys:NE treatments (3.25 to 4.88 g/Mcal) fed over 47 days. Results reported a greater linear improvement of growth and feed efficiency of Sp compared to Lp when increasing SID Lys:NE. Modelling the response to SID Lys:NE using quadratic polynomial models showed that the levels to reach 98% of maximum growth from day 0–47 were 3.67, 3.88, 4.06 g SID Lys/Mcal NE for Lp, Mp, and Sp, respectively. However, due to the overlapping SID Lys:NE confidence intervals at maximum performance, it was not possible to determine if requirements were different between BWCAT. Summarizing, the results suggested that feeding small pigs greater SID Lys:NE than large pigs can improve their performance and increase the efficiency of the overall production system.
doi:10.3390/ani10061032 pmid:32545783 fatcat:hfjat45whzaapacwvhku7rhaua

Natural Selection in the Great Apes

Alexander Cagan, Christoph Theunert, Hafid Laayouni, Gabriel Santpere, Marc Pybus, Ferran Casals, Kay Prüfer, Arcadi Navarro, Tomas Marques-Bonet, Jaume Bertranpetit, Aida M. Andrés
2016 Molecular biology and evolution  
Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both
more » ... urifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at
doi:10.1093/molbev/msw215 pmid:27795229 pmcid:PMC5100057 fatcat:eskizgdkufbm7lowzz27w7dyai
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