OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features in simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations with only a modest increase in cost.

OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features on simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein (GFP) chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations at only a modest increase in cost.

TALAIA: a 3D visual dictionary for protein structures.

MOTIVATION: Graphical analysis of the molecular structure of proteins can be very complex. Full-atom representations retain most geometric information but are generally crowded, and key structural patterns can be challenging to identify. Non-full-atom representations could be more instructive on physicochemical aspects but be insufficiently detailed regarding shapes (e.g. entity beans-like models in coarse grain approaches) or simple properties of amino acids (e.g. representation of superficial electrostatic properties). In this work, we present TALAIA a visual dictionary that aims to provide another layer of structural representations.TALAIA offers a visual grammar that combines simple representations of amino acids while retaining their general geometry and physicochemical properties. It uses unique objects, with differentiated shapes and colors to represent amino acids. It makes easier to spot crucial molecular information, including patches of amino acids or key interactions between side chains. Most conventions used in TALAIA are standard in chemistry and biochemistry, so experimentalists and modelers can rapidly grasp the meaning of any TALAIA depiction. RESULTS: We propose TALAIA as a tool that renders protein structures and encodes structure and physicochemical aspects as a simple visual grammar. The approach is fast, highly informative, and intuitive, allowing the identification of possible interactions, hydrophobic patches, and other characteristic structural features at first glance. The first implementation of TALAIA can be found at https://github.com/insilichem/talaia.

TeachOpenCADD 2022: open source and FAIR Python pipelines to assist in structural bioinformatics and cheminformatics research.

Computational pipelines have become a crucial part of modern drug discovery campaigns. Setting up and maintaining such pipelines, however, can be challenging and time-consuming-especially for novice scientists in this domain. TeachOpenCADD is a platform that aims to teach domain-specific skills and to provide pipeline templates as starting points for research projects. We offer Python-based solutions for common tasks in cheminformatics and structural bioinformatics in the form of Jupyter notebooks, based on open source resources only. Including the 12 newly released additions, TeachOpenCADD now contains 22 notebooks that cover both theoretical background as well as hands-on programming. To promote reproducible and reusable research, we apply software best practices to our notebooks such as testing with automated continuous integration and adhering to the idiomatic Python style. The new TeachOpenCADD website is available at https://projects.volkamerlab.org/teachopencadd and all code is deposited on GitHub.

Molecular Modeling for Artificial Metalloenzyme Design and Optimization.

Artificial metalloenzymes (ArMs) are obtained by inserting homogeneous catalysts into biological scaffolds and are among the most promising strategies in the quest for new-to-nature biocatalysts. The quality of their design strongly depends on how three partners interact: the biological host, the "artificial cofactor," and the substrate. However, structural characterization of functional artificial metalloenzymes by X-ray or NMR is often partial, elusive, or absent. How the cofactor binds to the protein, how the receptor reorganizes upon the binding of the cofactor and the substrate, and which are the binding mode(s) of the substrate for the reaction to proceed are key questions that are frequently unresolved yet crucial for ArM design. Such questions may eventually be solved by molecular modeling but require a step change beyond the current state-of-the-art methodologies.Here, we summarize our efforts in the study of ArMs, presenting both the development of computational strategies and their application. We first focus on our integrative computational framework that incorporates a variety of methods such as protein-ligand docking, classical molecular dynamics (MD), and pure quantum mechanical (QM) methods, which, when properly combined, are able to depict questions that range from host-cofactor binding predictions to simulations of entire catalytic mechanisms. We also pay particular attention to the protein-ligand docking strategies that we have developed to accurately predict the binding of transition metal-containing molecules to proteins. While this aspect is fundamental to many bioinorganic fields beyond ArMs, it has been disregarded from the molecular modeling landscape until very recently.Next we describe how to apply this computational framework to particular ArMs including systems previously characterized experimentally as well as others where computation served to guide the design. We start with the prediction of the interactions between homogeneous catalysts and biological hosts. Protein-ligand docking is pivotal at that stage, but it needs to be combined with QM/MM or MD approaches when the binding of the cofactor implies significant conformational changes of the protein or involve changes of the electronic state of the metal.Then, we summarize molecular modeling studies aimed at identifying cofactor-substrate arrangements inside the ArM active pocket that are consistent with its reactivity. These calculations stand on "Theozyme"-like dockings, MD-refined or not, which provide molecular rationale of the catalytic profiles of the artificial systems.In the third section, we present case studies to decode the entire catalytic mechanism of two ArMs: (1) an iridium based asymmetric transfer hydrogenase obtained by insertion of Noyori's catalyst into streptavidin and (2) a metallohydrolase achieved by including a receptor. Transition states, second coordination sphere effects, as well as motions of the cofactors are identified as drivers of the enantiomeric profiles.Finally, we report computer-aided designs of ArMs to guide experiments toward chemical and mutational changes that improve their activity and/or enantioselective profiles and expand toward future directions.

TeachOpenCADD-KNIME: A Teaching Platform for Computer-Aided Drug Design Using KNIME Workflows.

Open-source workflows have become more and more an integral part of computer-aided drug design (CADD) projects since they allow reproducible and shareable research that can be easily transferred to other projects. Setting up, understanding, and applying such workflows involves either coding or using workflow managers that offer a graphical user interface. We previously reported the TeachOpenCADD teaching platform that provides interactive Jupyter Notebooks (talktorials) on central CADD topics using open-source data and Python packages. Here we present the conversion of these talktorials to KNIME workflows that allow users to explore our teaching material without any line of code. TeachOpenCADD KNIME workflows are freely available on the KNIME Hub: https://hub.knime.com/volkamerlab/space/TeachOpenCADD .

Genetic Variants at the rs4720169 Locus of TBX20 and the rs12921862 Locus of AXIN1 May Increase the Risk of Congenital Heart Defects in the Mexican Population: A Pilot Study.

Background: Congenital heart defects (CHDs) are the most common type of birth defects and a major cause of infant mortality. Although knowledge of genetic risk variants for CHDs is scarce, most cases of CHDs are considered to be due to multifactorial inheritance. Objective: To analyze the association of 14 single nucleotide polymorphic variants previously associated with a risk of CHDs in a Mexican population with isolated CHDs. Materials and Methods: DNA samples obtained from healthy subjects and from subjects with isolated atrial, ventricular, or atrioventricular septal defects living in Northeastern Mexico were analyzed by real time-polymerase chain reaction for allelic discrimination of genetic variants of the genes TBX1, TBX20, ASTX-18-AS1, AXIN1, MTHFR, NKX2.5, BMP4, and NFATc1. The odds ratios (ORs) for allele and genotype frequencies and inheritance models were obtained. Results: Forty-two patients and 138 controls were included. Two variants were found to confer a risk of CHDs: variant rs4720169 of TBX20 in which the OR for the heterozygous state was 1.88 (95% confidence interval [CI]: 1.12-3.14, p = 0.010), whereas the OR for the homozygous state was 3.82 (95% CI: 1.18-12.3, p = 0.010); and variant rs12921862 of AXIN1 in which the OR for the heterozygous state was 4.15 (95% CI: 2.42-7.10; p ≤ 0.001), whereas the OR for the homozygous state was 9.2 (95% CI: 1.31-64.7, p = 0.008) for allele A. Conclusion: Genetic variants of the TBX20 and AXIN1 genes confer a significantly increased risk of congenital septal heart defects in a population from Northeastern Mexico.

Discovery of processive catalysis by an exo-hydrolase with a pocket-shaped active site.

Substrates associate and products dissociate from enzyme catalytic sites rapidly, which hampers investigations of their trajectories. The high-resolution structure of the native Hordeum exo-hydrolase HvExoI isolated from seedlings reveals that non-covalently trapped glucose forms a stable enzyme-product complex. Here, we report that the alkyl ß-D-glucoside and methyl 6-thio-ß-gentiobioside substrate analogues perfused in crystalline HvExoI bind across the catalytic site after they displace glucose, while methyl 2-thio-ß-sophoroside attaches nearby. Structural analyses and multi-scale molecular modelling of nanoscale reactant movements in HvExoI reveal that upon productive binding of incoming substrates, the glucose product modifies its binding patterns and evokes the formation of a transient lateral cavity, which serves as a conduit for glucose departure to allow for the next catalytic round. This path enables substrate-product assisted processive catalysis through multiple hydrolytic events without HvExoI losing contact with oligo- or polymeric substrates. We anticipate that such enzyme plasticity could be prevalent among exo-hydrolases.

Actualización en diagnóstico de divertículo de Meckel como causa de hemorragia gastrointestinal / Update in diagnosis of Meckel's diverticulum as a cause of gastrointestinal hemorrhage

El Divertículo de Meckel es la malformación congénita más común del sistema gastrointestinal1 , se produce al obliterarse el conducto onfalomesentérico a nivel proximal formando un divertículo verdadero en el borde anti mesentérico a nivel del íleon, el cual debería cerrarse entre la 5ta y 6ta semana de gestación normalmente. Sus alteraciones pueden dar lugar a pólipos ductales, bandas fibrosas, quistes ductales, fístulas íleoumbilicales o más frecuentemente al Divertículo de Meckel; estas variaciones pueden asociarse a otras malformaciones en el sistema nervioso o cardiovascular2 . Los remanentes onfalomesentéricos son más frecuentes en hombres que en mujeres, con una relación 2:1, siendo la incidencia general de un 2%3 . La mayoría de los casos se mantienen asintomáticos, pero algunos pacientes, sobre todo en edades pediátricas, pueden presentar síntomas como hemorragia gastrointestinal, torsión intestinal, obstrucción o infección4 . Dada su escasa e inespecífica sintomatología, es que podría llevar al clínico a confundirlo con otros diagnósticos diferenciales tales como la Enfermedad Inflamatoria Intestinal, Úlceras u otras patologías. Esta una de las razones por las que nos parece relevante realizar una revisión de las técnicas diagnósticas disponibles en la actualidad con el fin de determinar las mejores opciones diagnosticas dependiendo del medio en que se desenvuelva el clínico.

Meckel Diverticulum is the most common congenital malformation of the gastrointestinal system1 , it occurs when the omphalomesenteric duct is obliterated proximally, forming a true diverticulum in the anti-mesenteric border at the level of the ileum, which should be closed usually between the 5th and 6th week of gestation. Its alterations can give rise to ductal polyps, fibrous bands, ductal cysts, ileo-umbilical fistulas or more frequently to Meckel's diverticulum; These variations can be associated with other malformations in the nervous or cardiovascular system2 . Omphalomesenteric remnants are more frequent in men than in women, with a 2: 1 ratio, with a general incidence of 2% 3 . Most cases remain asymptomatic, but some patients, especially at pediatric ages, may present symptoms such as gastrointestinal bleeding, intestinal torsion, obstruction or infection4 . Given its scarce and unspecific symptomatology, it could lead the clinician to confuse it with other differential diagnoses such as Inflammatory Bowel Disease, Ulcers or other pathologies. This is one of the reasons why it seems relevant to review the diagnostic techniques currently available to determine the best diagnostic options depending on the environment in which the clinician operates

Yasuní--a hotspot for jaguars Panthera onca (Carnivora: Felidae)? Camera-traps and jaguar activity at Tiputini Biodiversity Station, Ecuador.

Jaguars (Panthera onca) are the largest predator in lowland forests of Amazonia but there have been few studies on their occurrence and activity in such forests. Here, we used camera traps to document the occurrence and activity of jaguars within a local area (-650ha) of lowland forest of Eastern Ecuador, over two sample periods (2005-2008, 7 222 trap days; 2010-2012, 6 199 trap days). We accumulated 151 independent photos of jaguars (189 total photographs) that represented 21 different individuals, including 11 males (114 photographs), seven females (32 photographs), and three that could not be assigned to a sex. Individual jaguars varied in the number of months they were recorded in the area; ten were photographed in only one month; five were photographed over periods of 8 to 22 months; and five from 45 to 81 months. Capture rates across all camera stations averaged 10.6/1 000 trap days; capture rates did not differ between the two sample periods. Male jaguars were more active during the day (06:00am-18:00pm; 71% of photographs), whereas females were equally active during the day and night. Monthly activity was variable but showed no consistent pattern. Although the study area is much smaller than typical home ranges of jaguars, the area is clearly visited by a large number of different individuals, some of whom repeatedly visit the area, indicating that it forms part of their home range. Other individuals likely were simply passing through the area. Based on the number of jaguars recorded during this study, it is clear that the region is an important area for conservation. Continued protection will be needed to ensure that populations ofjaguars and other species remain viable.

Yasuní - a hotspot for jaguars Panthera onca (Carnivora: Felidae)? Camera-traps and jaguar activity at Tiputini Biodiversity Station, Ecuador / Yasuní - Un hotspot para jaguares Panthera onca (Carnivora: Felidae)? Cámaras trampa y actividad del jaguar en la Estación de Biodiversidad Tiputini, Ecuador

Jaguars (Panthera onca) are the largest predator in lowland forests of Amazonia but there have been few studies on their occurrence and activity in such forests. Here, we used camera traps to document the occurrence and activity of jaguars within a local area (~650ha) of lowland forest of Eastern Ecuador, over two sample periods (2005-2008, 7 222 trap days; 2010-2012, 6 199 trap days). We accumulated 151 independent photos of jaguars (189 total photographs) that represented 21 different individuals, including 11 males (114 photographs), seven females (32 photographs), and three that could not be assigned to a sex. Individual jaguars varied in the number of months they were recorded in the area; ten were photographed in only one month; five were photographed over periods of 8 to 22 months; and five from 45 to 81 months. Capture rates across all camera stations averaged 10.6/1 000 trap days; capture rates did not differ between the two sample periods. Male jaguars were more active during the day (06:00am-18:00pm; 71% of photographs), whereas females were equally active during the day and night. Monthly activity was variable but showed no consistent pattern. Although the study area is much smaller than typical home ranges of jaguars, the area is clearly visited by a large number of different individuals, some of whom repeatedly visit the area, indicating that it forms part of their home range. Other individuals likely were simply passing through the area. Based on the number of jaguars recorded during this study, it is clear that the region is an important area for conservation. Continued protection will be needed to ensure that populations of jaguars and other species remain viable. Rev. Biol. Trop. 62 (2): 689-698. Epub 2014 June 01.

El jaguar (Panthera onca) es el depredador más grande de los bosques bajos de la Amazonía, pero existen pocos estudios sobre su presencia y actividad en los mismos. En este estudio utilizamos cámaras trampa para documentar la presencia y actividad de jaguares dentro de una área de bosque bajo de la Amazonía este de Ecuador (~650 ha) en dos períodos (2005-2008, 7 222 trampas noche; 2010-2012, 6 199 trampas noche). Acumulamos 151 fotos independientes de jaguares (189 fotografías en total) que representaron 21 individuos, incluyendo 11 machos (114 fotos), siete hembras (32 fotos) y tres a los que no se les pudo asignar sexo. Los jaguares individuales variaron en el número de meses en que fueron registrados en el área; diez fueron fotografiados solo en un mes; cinco fueron fotografiados en un periodo entre 8 y 22 meses; y cinco jaguares entre 45 y 81. Las tasas de captura a través de las estaciones de trampeo promediaron 10.6/1 000 trampas noche; las tasas de captura no presentaron diferencias en los dos períodos de muestreo. Los jaguares machos fueron más activos durante el día (06:00am-18:00pm; 71% de las fotografías) mientras que las hembras fueron igualmente activas tanto en el día como en la noche. La actividad mensual fue variable pero no mostró un patrón consistente. Aunque el área de estudio es mucho más pequeña que el rango de vida típico para un jaguar, el área es claramente visitada por un alto número de individuos diferentes, algunos de los cuales visitan repetidamente el lugar, indicando que este forma parte de su rango de vida. Es probable que otros individuos solamente sean transeúntes del área.

LIMITED GEOGRAPHIC VARIATION IN THE VOCALIZATIONS OF THE ENDANGERED THICK-BILLED PARROT: IMPLICATIONS FOR CONSERVATION STRATEGIES.

The populations of many species are declining worldwide, and conservation efforts struggle to keep pace with extinction rates. Conservation biologists commonly employ strategies such as translocation and reintroduction, which move individuals of endangered species from one part of their range to another. Because individuals from endangered populations are nonexpendable, identifying any potential barriers to the establishment of viable populations prior to release of individuals should be a priority. This study evaluates the potential for learned communication signals to constrain conservation strategies such as reintroduction in an endangered species, the Thick-billed Parrot (Rhynchopsitta pachyrhyncha). We conducted vocal surveys at three geographically distinct breeding populations in the Sierra Madre Occidental of Chihuahua, Mexico. Acoustic analyses utilizing both spectrogram cross-correlations and parameter measurements from spectrograms revealed no significant differences among the three sites in two common call types. Calls did vary among individuals within a site. The apparent lack of significant geographic variation across sampled sites suggests that differences in learned communication signals are unlikely to pose a barrier to the integration of translocated individuals from different populations into newly established populations.

[Environmental tobacco smoke and pneumonia in children living in Monterrey, México]. / Humo de Tabaco Ambiental y Neumonías en Niños de Monterrey, México.

OBJECTIVE: Acute respiratory diseases occupy the first 5 places in infantile morbidity and mortality around the world, two million children directly dying from such cause annually. Environmental tobacco smoke (ETS) contains toxic and irritating compounds having an injurious effect on health, producing increased risk of morbidity and mortality in non-smoking adults and children. Our main objective was determining the association between ETS and pneumonia in children. MATERIAL AND METHODS: This was an unmatched case and controls hospital-based study. Odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 285 patients (142 cases and 143 controls) were studied; 47,4 % of the patients were female and average age was 4,5,+2,7. OR for patients being exposed to ETS developing pneumonia was 3,44 (CI: 2,11-5,6). DISCUSSION: Children being exposed to ETS increases the risk of developing pneumonia by more than threefold.

Humo de Tabaco Ambiental y Neumonías en Niños de Monterrey, México / Environmental tobacco smoke and pneumonia in children living in Monterrey, México

Objetivo Las enfermedades respiratorias agudas ocupan en el mundo los primeros 5 lugares en morbilidad y mortalidad infantil, anualmente mueren más de dos millones de niños por esa causa. El humo del tabaco ambiental (HTA) contiene compuestos irritantes y tóxicos nocivos para la salud, que incrementan el riesgo de morbilidad y mortalidad en lactantes, niños y adultos no fumadores. Nuestro principal objetivo fue determinar la asociación entre HTA y la presencia de neumonías en niños. Material y métodos Se realizó un estudio de casos y controles no pareados. Se calcularon las razones de momios (RM) e intervalo de confianza 95 por ciento (IC) para cada variable. Resultados Se analizaron 285 pacientes, 142 casos y 143 controles, 47,4 por ciento femeninos, la edad promedio fue 4,5+2,7 años. La RM para expuestos al HTA fue 3,44, IC 2,1- 5,6. Discusión La exposición a HTA incrementa más de tres veces el riesgo de padecer neumonías en niños.

Objective Acute respiratory diseases occupy the first 5 places in infantile morbidity and mortality around the world, two million children directly dying from such cause annually. Environmental tobacco smoke (ETS) contains toxic and irritating compounds having an injurious effect on health, producing increased risk of morbidity and mortality in non-smoking adults and children. Our main objective was determining the association between ETS and pneumonia in children. Material and methods This was an unmatched case and controls hospital-based study. Odds ratio (OR) and 95 percent confidence interval (CI) were calculated. Results A total of 285 patients (142 cases and 143 controls) were studied; 47,4 percent of the patients were female and average age was 4,5,+2,7. OR for patients being exposed to ETS developing pneumonia was 3,44 (CI: 2,11-5,6). Discussion Children being exposed to ETS increases the risk of developing pneumonia by more than threefold.