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Article ; Online: Improving the Thermostability of Xylanase A from

Ngo, Khoa / Bruno da Silva, Fernando / Leite, Vitor B P / Contessoto, Vinícius G / Onuchic, José N

The journal of physical chemistry. B

2021 Volume 125, Issue 17, Page(s) 4359–4367

Abstract: The rational improvement of the enzyme catalytic activity is one of the most significant challenges in biotechnology. Most conventional strategies used to engineer enzymes involve selecting mutations to increase their thermostability. Determining good ... ...

Abstract	The rational improvement of the enzyme catalytic activity is one of the most significant challenges in biotechnology. Most conventional strategies used to engineer enzymes involve selecting mutations to increase their thermostability. Determining good criteria for choosing these substitutions continues to be a challenge. In this work, we combine bioinformatics, electrostatic analysis, and molecular dynamics to predict beneficial mutations that may improve the thermostability of XynA from
MeSH term(s)	Bacillus subtilis/genetics ; Bacillus subtilis/metabolism ; Bacterial Proteins/genetics ; Computational Biology ; Endo-1,4-beta Xylanases/genetics ; Endo-1,4-beta Xylanases/metabolism ; Enzyme Stability ; Mutation ; Static Electricity
Chemical Substances	Bacterial Proteins ; Endo-1,4-beta Xylanases (EC 3.2.1.8)
Language	English
Publishing date	2021-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.1c01253
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Article: Comprehensive and accurate genome analysis at scale using DRAGEN accelerated algorithms.

Behera, Sairam / Catreux, Severine / Rossi, Massimiliano / Truong, Sean / Huang, Zhuoyi / Ruehle, Michael / Visvanath, Arun / Parnaby, Gavin / Roddey, Cooper / Onuchic, Vitor / Cameron, Daniel L / English, Adam / Mehtalia, Shyamal / Han, James / Mehio, Rami / Sedlazeck, Fritz J

bioRxiv : the preprint server for biology

2024

Abstract: Research and medical genomics require comprehensive and scalable solutions to drive the discovery of novel disease targets, evolutionary drivers, and genetic markers with clinical significance. This necessitates a framework to identify all types of ... ...

Abstract	Research and medical genomics require comprehensive and scalable solutions to drive the discovery of novel disease targets, evolutionary drivers, and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size (e.g., SNV/SV) or location (e.g., repeats). Here we present DRAGEN that utilizes novel methods based on multigenomes, hardware acceleration, and machine learning based variant detection to provide novel insights into individual genomes with ~30min computation time (from raw reads to variant detection). DRAGEN outperforms all other state-of-the-art methods in speed and accuracy across all variant types (SNV, indel, STR, SV, CNV) and further incorporates specialized methods to obtain key insights in medically relevant genes (e.g., HLA, SMN, GBA). We showcase DRAGEN across 3,202 genomes and demonstrate its scalability, accuracy, and innovations to further advance the integration of comprehensive genomics for research and medical applications.
Language	English
Publishing date	2024-01-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.02.573821
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Article ; Online: Modeling Chikungunya control strategies and Mayaro potential outbreak in the city of Rio de Janeiro.

Dodero-Rojas, Esteban / Ferreira, Luiza G / Leite, Vitor B P / Onuchic, José N / Contessoto, Vinícius G

PloS one

2020 Volume 15, Issue 1, Page(s) e0222900

Abstract: Mosquito-borne diseases have become a significant health issue in many regions around the world. For tropical countries, diseases such as Dengue, Zika, and Chikungunya, became epidemic in the last decades. Health surveillance reports during this period ... ...

Abstract	Mosquito-borne diseases have become a significant health issue in many regions around the world. For tropical countries, diseases such as Dengue, Zika, and Chikungunya, became epidemic in the last decades. Health surveillance reports during this period were crucial in providing scientific-based information to guide decision making and resources allocation to control outbreaks. In this work, we perform data analysis of the last Chikungunya epidemics in the city of Rio de Janeiro by applying a compartmental mathematical model. Sensitivity analyses were performed in order to describe the contribution of each parameter to the outbreak incidence. We estimate the "basic reproduction number" for those outbreaks and predict the potential epidemic outbreak of the Mayaro virus. We also simulated several scenarios with different public interventions to decrease the number of infected people. Such scenarios should provide insights about possible strategies to control future outbreaks.
MeSH term(s)	Animals ; Basic Reproduction Number ; Brazil/epidemiology ; Chikungunya Fever/epidemiology ; Chikungunya Fever/virology ; Chikungunya virus/pathogenicity ; Disease Outbreaks ; Epidemics/prevention & control ; Humans ; Insect Vectors/virology ; Models, Theoretical ; Mosquito Vectors/virology
Language	English
Publishing date	2020-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0222900
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method.

Sanches, Murilo N / Knapp, Kaitlin / Oliveira, Antonio B / Wolynes, Peter G / Onuchic, José N / Leite, Vitor B P

The journal of physical chemistry. B

2021 Volume 126, Issue 1, Page(s) 93–99

Abstract: The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation ... ...

Abstract	The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer's disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides/genetics ; Amyloid beta-Protein Precursor ; Humans ; Intrinsically Disordered Proteins ; Protein Isoforms
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Intrinsically Disordered Proteins ; Protein Isoforms
Language	English
Publishing date	2021-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.1c08525
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Article ; Online: Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms.

Oliveira Junior, Antonio B / Lin, Xingcheng / Kulkarni, Prakash / Onuchic, José N / Roy, Susmita / Leite, Vitor B P

Journal of chemical theory and computation

2021 Volume 17, Issue 5, Page(s) 3178–3187

Abstract: Intrinsically disordered proteins (IDPs) lack a rigid three-dimensional structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction ... ...

Abstract	Intrinsically disordered proteins (IDPs) lack a rigid three-dimensional structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed energy landscape visualization method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, prostate-associated gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely, HIPK1 and CLK2, phosphorylate PAGE4, generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyperphosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield, and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool, especially to analyze the highly frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.
MeSH term(s)	Amino Acid Sequence ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/metabolism ; Phosphorylation ; Protein Conformation ; Protein Isoforms/chemistry ; Protein Isoforms/metabolism ; Reproducibility of Results ; Sequence Homology, Amino Acid
Chemical Substances	Intrinsically Disordered Proteins ; Protein Isoforms
Language	English
Publishing date	2021-04-19
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.1c00027
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Article: Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method

Sanches, Murilo N. / Knapp, Kaitlin / Oliveira, Antonio B. / Wolynes, Peter G. / Onuchic, José N. / Leite, Vitor B. P.

Journal of physical chemistry. 2021 Dec. 30, v. 126, no. 1

2021

Abstract	The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.
Keywords	amino acids ; amyloid ; energy ; models ; peptides ; physical chemistry
Language	English
Dates of publication	2021-1230
Size	p. 93-99.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021/acs.jpcb.1c08525
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Intrinsically disordered proteins: Ensembles at the limits of Anfinsen's dogma.

Kulkarni, Prakash / Leite, Vitor B P / Roy, Susmita / Bhattacharyya, Supriyo / Mohanty, Atish / Achuthan, Srisairam / Singh, Divyoj / Appadurai, Rajeswari / Rangarajan, Govindan / Weninger, Keith / Orban, John / Srivastava, Anand / Jolly, Mohit Kumar / Onuchic, Jose N / Uversky, Vladimir N / Salgia, Ravi

Biophysics reviews

2022 Volume 3, Issue 1, Page(s) 11306

Abstract: Intrinsically disordered proteins (IDPs) are proteins that lack rigid 3D structure. Hence, they are often misconceived to present a challenge to Anfinsen's dogma. However, IDPs exist as ensembles that sample a quasi-continuum of rapidly interconverting ... ...

Abstract	Intrinsically disordered proteins (IDPs) are proteins that lack rigid 3D structure. Hence, they are often misconceived to present a challenge to Anfinsen's dogma. However, IDPs exist as ensembles that sample a quasi-continuum of rapidly interconverting conformations and, as such, may represent proteins at the extreme limit of the Anfinsen postulate. IDPs play important biological roles and are key components of the cellular protein interaction network (PIN). Many IDPs can interconvert between disordered and ordered states as they bind to appropriate partners. Conformational dynamics of IDPs contribute to conformational noise in the cell. Thus, the dysregulation of IDPs contributes to increased noise and "promiscuous" interactions. This leads to PIN rewiring to output an appropriate response underscoring the critical role of IDPs in cellular decision making. Nonetheless, IDPs are not easily tractable experimentally. Furthermore, in the absence of a reference conformation, discerning the energy landscape representation of the weakly funneled IDPs in terms of reaction coordinates is challenging. To understand conformational dynamics in real time and decipher how IDPs recognize multiple binding partners with high specificity, several sophisticated knowledge-based and physics-based
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2688-4089
ISSN (online)	2688-4089
DOI	10.1063/5.0080512
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Article ; Online: Modeling Chikungunya control strategies and Mayaro potential outbreak in the city of Rio de Janeiro.

Esteban Dodero-Rojas / Luiza G Ferreira / Vitor B P Leite / José N Onuchic / Vinícius G Contessoto

PLoS ONE, Vol 15, Iss 1, p e

2020 Volume 0222900

Abstract	Mosquito-borne diseases have become a significant health issue in many regions around the world. For tropical countries, diseases such as Dengue, Zika, and Chikungunya, became epidemic in the last decades. Health surveillance reports during this period were crucial in providing scientific-based information to guide decision making and resources allocation to control outbreaks. In this work, we perform data analysis of the last Chikungunya epidemics in the city of Rio de Janeiro by applying a compartmental mathematical model. Sensitivity analyses were performed in order to describe the contribution of each parameter to the outbreak incidence. We estimate the "basic reproduction number" for those outbreaks and predict the potential epidemic outbreak of the Mayaro virus. We also simulated several scenarios with different public interventions to decrease the number of infected people. Such scenarios should provide insights about possible strategies to control future outbreaks.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: ToPS: a framework to manipulate probabilistic models of sequence data.

Kashiwabara, André Yoshiaki / Bonadio, Igor / Onuchic, Vitor / Amado, Felipe / Mathias, Rafael / Durham, Alan Mitchell

PLoS computational biology

2013 Volume 9, Issue 10, Page(s) e1003234

Abstract: Discrete Markovian models can be used to characterize patterns in sequences of values and have many applications in biological sequence analysis, including gene prediction, CpG island detection, alignment, and protein profiling. We present ToPS, a ... ...

Abstract	Discrete Markovian models can be used to characterize patterns in sequences of values and have many applications in biological sequence analysis, including gene prediction, CpG island detection, alignment, and protein profiling. We present ToPS, a computational framework that can be used to implement different applications in bioinformatics analysis by combining eight kinds of models: (i) independent and identically distributed process; (ii) variable-length Markov chain; (iii) inhomogeneous Markov chain; (iv) hidden Markov model; (v) profile hidden Markov model; (vi) pair hidden Markov model; (vii) generalized hidden Markov model; and (viii) similarity based sequence weighting. The framework includes functionality for training, simulation and decoding of the models. Additionally, it provides two methods to help parameter setting: Akaike and Bayesian information criteria (AIC and BIC). The models can be used stand-alone, combined in Bayesian classifiers, or included in more complex, multi-model, probabilistic architectures using GHMMs. In particular the framework provides a novel, flexible, implementation of decoding in GHMMs that detects when the architecture can be traversed efficiently.
MeSH term(s)	Bayes Theorem ; Computational Biology/methods ; CpG Islands/genetics ; Markov Chains ; Sequence Analysis/methods
Language	English
Publishing date	2013-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1003234
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Article ; Online: ToPS

André Yoshiaki Kashiwabara / Igor Bonadio / Vitor Onuchic / Felipe Amado / Rafael Mathias / Alan Mitchell Durham

PLoS Computational Biology, Vol 9, Iss 10, p e

a framework to manipulate probabilistic models of sequence data.

2013 Volume 1003234

Abstract	Discrete Markovian models can be used to characterize patterns in sequences of values and have many applications in biological sequence analysis, including gene prediction, CpG island detection, alignment, and protein profiling. We present ToPS, a computational framework that can be used to implement different applications in bioinformatics analysis by combining eight kinds of models: (i) independent and identically distributed process; (ii) variable-length Markov chain; (iii) inhomogeneous Markov chain; (iv) hidden Markov model; (v) profile hidden Markov model; (vi) pair hidden Markov model; (vii) generalized hidden Markov model; and (viii) similarity based sequence weighting. The framework includes functionality for training, simulation and decoding of the models. Additionally, it provides two methods to help parameter setting: Akaike and Bayesian information criteria (AIC and BIC). The models can be used stand-alone, combined in Bayesian classifiers, or included in more complex, multi-model, probabilistic architectures using GHMMs. In particular the framework provides a novel, flexible, implementation of decoding in GHMMs that detects when the architecture can be traversed efficiently.
Keywords	Biology (General) ; QH301-705.5
Subject code	006
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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