Ignacio E. Sánchez

Fundación Ciencias Exactas y Naturales

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G. Gay

Fundación Instituto Leloir

Lucía B. Chemes

Consejo Nacional de Investigaciones Científicas y Técnicas

Diego U. Ferreiro

University of Buenos Aires

Leonardo G. Alonso

University of Buenos Aires

Ariel A. Aptekmann

Hackensack Meridian Health

Juliana Glavina

Consejo Nacional de Investigaciones Científicas y Técnicas

Ramiro Lorenzo

Université Libre de Bruxelles

Geert Jan van Gelder

University of Oxford

Thomas Kiefhaber

Martin Luther University Halle-Wittenberg

Alfonso Soler‐Bistué

Universidad Nacional de San Martín

Cooperative Institutions

Consejo Nacional de Investigaciones Científicas y Técnicas

University of Buenos Aires

Fundación Ciencias Exactas y Naturales

Fundación Instituto Leloir

Hospital Del Mar

Parc de Salut

European Molecular Biology Laboratory

Centre National de la Recherche Scientifique

National Institutes of Health

European Molecular Biology Laboratory

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Optimal threshold estimation for binary classifiers using game theory

F1000Research (2016)

Ignacio E. Sánchez

Many bioinformatics algorithms can be understood as binary classifiers. They are usually trained by maximizing the area under the receiver operating characteristic (ROC) curve. On the other hand, choosing the best threshold for practical use is a complex task, due to uncertain and context-dependent skews in the abundance of positives in nature and in the yields/costs for correct/incorrect classification. We argue that considering a classifier as a player in a zero-sum game allows us to use the minimax principle from game theory to determine the optimal operating point. The proposed classifier threshold corresponds to the intersection between the ROC curve and the descending diagonal in ROC space and yields a minimax accuracy of 1-FPR. Our proposal can be readily implemented in practice, and reveals that the empirical condition for threshold estimation of “specificity equals sensitivity” maximizes robustness against uncertainties in the abundance of positives in nature and classification costs.

Binary classification

10.12688/f1000research.10114.2

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Citations (3)

Solvent constraints for biopolymer folding and evolution in extraterrestrial environments

arXiv (Cornell University) (2023)

Ignacio E. Sánchez Ezequiel A. Galpern Diego U. Ferreiro

We propose that spontaneous folding and molecular evolution of biopolymers are two universal aspects that must concur for life to happen. These aspects are fundamentally related to the chemical composition of biopolymers and crucially depend on the solvent in which they are embedded. We show that molecular information theory and energy landscape theory allow us to explore the limits that solvents impose on biopolymer existence. We consider 54 solvents, including water, alcohols, hydrocarbons, halogenated solvents, aromatic solvents, and low molecular weight substances made up of elements abundant in the universe, which may potentially take part in alternative biochemistries. We find that along with water, there are many solvents for which the liquid regime is compatible with biopolymer folding and evolution. We present a ranking of the solvents in terms of biopolymer compatibility. Many of these solvents have been found in molecular clouds or may be expected to occur in extrasolar planets.

Biopolymer

Folding (DSP implementation)

Abiogenesis

10.48550/arxiv.2310.00067

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A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

Biomolecules (2021)

Eva S. Cobos Ignacio E. Sánchez Lucía B. Chemes José C. Martínez Javier Murciano‐Calles

PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. With such an array of relevant and diverse interactions, PDZ binding specificity has been thoroughly studied and a traditional classification has grouped PDZ domains in three major specificity classes. In this work, we have selected four human PDZ domains covering the three canonical specificity-class binding mode and a set of their corresponding binders, including host/natural, viral and designed PDZ motifs. Through calorimetric techniques, we have covered the entire cross interactions between the selected PDZ domains and partners. The results indicate a rather basic specificity in each PDZ domain, with two of the domains that bind their cognate and some non-cognate ligands and the two other domains that basically bind their cognate partners. On the other hand, the host partners mostly bind their corresponding PDZ domain and, interestingly, the viral ligands are able to bind most of the studied PDZ domains, even those not previously described. Some viruses may have evolved to use of the ability of the PDZ fold to bind multiple targets, with resulting affinities for the virus–host interactions that are, in some cases, higher than for host–host interactions.

PDZ domain

10.3390/biom11081071

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Non-linear rate-equilibrium free energy relationships and Hammond behavior in protein folding

Biophysical Chemistry (2002)

Ignacio E. Sánchez Thomas Kiefhaber

Folding (DSP implementation)

Limiting

10.1016/s0301-4622(02)00294-6

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Citations (58)

‮الباب العاشر في طبقات الأطباء العراقيين وأطباء الجزيرة وديار بكر‬‎

BRILL eBooks (2019)

Alasdair Watson Geert Jan van Gelder Ignacio E. Sánchez

10.1163/9789004545571_028

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Detecting Repetitions and Periodicities in Proteins by Tiling the Structural Space

arXiv (Cornell University) (2013)

R. Gonzalo Parra Rocío Espada Ignacio E. Sánchez Manfred J. Sippl Diego U. Ferreiro

The notion of energy landscapes provides conceptual tools for understanding the complexities of protein folding and function. Energy Landscape Theory indicates that it is much easier to find sequences that satisfy the "Principle of Minimal Frustration" when the folded structure is symmetric (Wolynes, P. G. Symmetry and the Energy Landscapes of Biomolecules. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14249-14255). Similarly, repeats and structural mosaics may be fundamentally related to landscapes with multiple embedded funnels. Here we present analytical tools to detect and compare structural repetitions in protein molecules. By an exhaustive analysis of the distribution of structural repeats using a robust metric we define those portions of a protein molecule that best describe the overall structure as a tessellation of basic units. The patterns produced by such tessellations provide intuitive representations of the repeating regions and their association towards higher order arrangements. We find that some protein architectures can be described as nearly periodic, while in others clear separations between repetitions exist. Since the method is independent of amino acid sequence information we can identify structural units that can be encoded by a variety of distinct amino acid sequences.

Tessellation (computer graphics)

Energy landscape

Folding (DSP implementation)

Sequence space

Sequence (biology)

Quantitative biology

10.48550/arxiv.1306.2852

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167P KRAS G12C lung adenocarcinoma represents a distinct group of patients with different response to immunotherapy

Annals of Oncology (2022)

L. Masfarré Priscila Mendes Maia Rocha S. Clavé Laura Moliner N. Navarro-Gorro

10.1016/j.annonc.2022.02.199

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Synthetic Crossfeeding Cocultures in Yeast: Computational Model of Autoregulation and Design of a Tryptophan Export Device

Journal of Synthetic Biology (2015)

Alan Bush Manuel Giménez Alicia Grande Luciano Gastón Morosi Verónica Parasco

In order to contribute to the design of crossfeeding systems, we modeled population control in a coculture of two crossfeeding strains of an organism, each of which secretes a metabolite the other strain requires to grow. Differential equations show that the steady-state population ratio can be tuned by varying the ratio of the metabolite secretion rates, as long as they fall within a range determined by the nature of the organism. Numerical simulations of Trp/His crossfeeding in budding yeast suggest that the time required to reach steady state populations critically depends on the capacity of the cells to uptake the crossfeeding amino acids. We also engineered and evaluated a novel genetic device that secretes tryptophan-rich peptides with a cell penetrating sequence. Experimental validation showed that the device increases tryptophan secretion and enables growth of a trp − strain in a coculture in synthetic medium lacking tryptophan.

Strain (injury)

Model Organism

10.1155/2015/178514

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Citations (1)

55P Differences in response to immune treatment between KRAS G12C and KRAS non-G12C mutated non-small cell lung cancer

ESMO Open (2024)

L. Masfarre Pinto A.S. De Freitas Matos-Parreira N. Castro Unanua P.F. Simoes Da Rocha Irune Ruiz

Non-small cell lung cancer (NSCLC) can harbor different KRAS mutations. Although targeted therapy is available for KRAS G12C-mutant (mt) NSCLC, immune checkpoint inhibitors (ICIs) are still the first line treatment (tx) for these patients (pts). Here we aimed to assess the outcomes on ICIs for KRAS G12C compared to KRAS non-G12C-mt pts. This is an updated observational, retrospective, multicenter study of pts with KRAS-mt NSCLC treated with ICIs between January 2017 and October 2023. 14 pts received anti-KRAS G12C tx. Targeted sequencing was performed in 59% cases and polymerase chain reaction in the rest. Clinicopathological and molecular data were collected. We evaluated the characteristics, tx response and survival outcomes on ICIs of pts with KRAS G12C vs non-G12C-mt tumors. 189 pts were included with a median follow-up of 34.3 months (m). STK11 and TP53 were the most frequent co-mutated genes present in 4.3%/18.5% G12C/non-G12C and 21.3%/44.7% G12C/non-G12C, respectively. In all KRAS mt tumors, harboring a TP53 co-mutation was associated to a positive PD-L1 and a better ECOG (p < 0.001 and p=0.006, respectively). In addition, a trend to a better overall survival (OS) was seen in TP53 vs STK11 tumors (14.7 vs 6.1m, respectively, p = 0.195). No differences were seen in the median duration of response or progression free survival between G12C/non-G12C (10.7 vs 9.5m p=0.202 and 8 vs 5m p= 0.554, respectively). KRAS G12C tumors were associated with a better median OS compared with non-G12C tumors (16.2 vs 9.2m p=0.024). In the multivariate analysis for OS, PD-L1 negative tumors and ECOG ≥1 were independently associated with worse OS (p=0.004 and p<0.001, respectively).Table: 55PN (%)G12C (n=92)Non-G12C (n=97)p-valueMedian age (range)62.9 (61.8-64.9)65 (63-66.3)Sex0.237Male36 (39.1)67 (69.1)Female56 (60.9)30 (30.9)Tobacco0.866Former47 (51.1)49 (50.5)Current44 (47.8)46 (47.4)Stage0.530I-III18 (19.6)23 (23.7)IV74 (80.4)74 (76.3)M1 CNS17 (18.5)26 (26.8)0.172M1 liver16 (17.4)19 (19.6)0.698ICIs treatment line0.466172 (78.3)80 (82.5)≥220 (21.7)17 (17.5)PD-L10.234Negative (0%)22 (23.9)32 (33)Positive (≥1%)64 (69.6)63 (65)ECOG0.241034 (37)44 (45.4)≥158 (63)53 (54.6) Open table in a new tab Our work shows that pts with KRAS G12C tumors are associated with better OS on ICIs tx when compared with pts with KRAS non-G12C tumors. Harboring a TP53 co-mutation associated to a KRAS mutation might determine a different tumor microenvironment and therefore a better response to ICI tx.

10.1016/j.esmoop.2024.102634

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Citations (1)

Characterization of Protein Folding Barriers with Rate Equilibrium Free Energy Relationships

Thomas Kiefhaber Ignacio E. Sánchez Annett Bachmann

Folding (DSP implementation)

Characterization

10.1002/9783527619498.ch12b

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Citations (6)