HotRegion: a database of predicted hot spot clusters

Hot spots are energetically important residues at protein interfaces and they are not randomly distributed across the interface but rather clustered. These clustered hot spots form hot regions. Hot regions are important for the stability of protein complexes, as well as providing specificity to binding sites. We propose a database called HotRegion, which provides the hot region information of the interfaces by using predicted hot spot residues, and structural properties of these interface residues such as pair potentials of interface residues, accessible surface area (ASA) and relative ASA values of interface residues of both monomer and complex forms of proteins. Also, the 3D visualization of the interface and interactions among hot spot residues are provided. HotRegion is accessible at http://prism.ccbb.ku.edu.tr/hotregion

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society

Tradeoff Between Stability and Multispecificity in the Design of Promiscuous Proteins

Natural proteins often partake in several highly specific protein-protein interactions. They are thus subject to multiple opposing forces during evolutionary selection. To be functional, such multispecific proteins need to be stable in complex with each interaction partner, and, at the same time, to maintain affinity toward all partners. How is this multispecificity acquired through natural evolution? To answer this compelling question, we study a prototypical multispecific protein, calmodulin (CaM), which has evolved to interact with hundreds of target proteins. Starting from high-resolution structures of sixteen CaM-target complexes, we employ state-of-the-art computational methods to predict a hundred CaM sequences best suited for interaction with each individual CaM target. Then, we design CaM sequences most compatible with each possible combination of two, three, and all sixteen targets simultaneously, producing almost 70,000 low energy CaM sequences. By comparing these sequences and their energies, we gain insight into how nature has managed to find the compromise between the need for favorable interaction energies and the need for multispecificity. We observe that designing for more partners simultaneously yields CaM sequences that better match natural sequence profiles, thus emphasizing the importance of such strategies in nature. Furthermore, we show that the CaM binding interface can be nicely partitioned into positions that are critical for the affinity of all CaM-target complexes and those that are molded to provide interaction specificity. We reveal several basic categories of sequence-level tradeoffs that enable the compromise necessary for the promiscuity of this protein. We also thoroughly quantify the tradeoff between interaction energetics and multispecificity and find that facilitating seemingly competing interactions requires only a small deviation from optimal energies. We conclude that multispecific proteins have been subjected to a rigorous optimization process that has fine-tuned their sequences for interactions with a precise set of targets, thus conferring their multiple cellular functions

The modular organization of domain structures: insights into protein-protein binding.

Domains are the building blocks of proteins and play a crucial role in protein-protein interactions. Here, we propose a new approach for the analysis and prediction of domain-domain interfaces. Our method, which relies on the representation of domains as residue-interacting networks, finds an optimal decomposition of domain structures into modules. The resulting modules comprise highly cooperative residues, which exhibit few connections with other modules. We found that non-overlapping binding sites in a domain, involved in different domain-domain interactions, are generally contained in different modules. This observation indicates that our modular decomposition is able to separate protein domains into regions with specialized functions. Our results show that modules with high modularity values identify binding site regions, demonstrating the predictive character of modularity. Furthermore, the combination of modularity with other characteristics, such as sequence conservation or surface patches, was found to improve our predictions. In an attempt to give a physical interpretation to the modular architecture of domains, we analyzed in detail six examples of protein domains with available experimental binding data. The modular configuration of the TEM1-beta-lactamase binding site illustrates the energetic independence of hotspots located in different modules and the cooperativity of those sited within the same modules. The energetic and structural cooperativity between intramodular residues is also clearly shown in the example of the chymotrypsin inhibitor, where non-binding site residues have a synergistic effect on binding. Interestingly, the binding site of the T cell receptor beta chain variable domain 2.1 is contained in one module, which includes structurally distant hot regions displaying positive cooperativity. These findings support the idea that modules possess certain functional and energetic independence. A modular organization of binding sites confers robustness and flexibility to the performance of the functional activity, and facilitates the evolution of protein interactions

Systematic Review of Oculo-Visual and Musculoskeletal Alterations Associated with Visual Display Terminals Work

Revisión[ES] Introducción: Los cambios en el mundo del trabajo y la introducción de nuevas tecnologías en los últimos años han propiciado el aumento del uso de pantallas de visualización de datos (PVD) en multitud de puestos de trabajo. El malestar y los síntomas que se experimentan durante el uso de PVD pueden tener un impacto importante en términos de calidad, —derivado del aumento en el número de errores que se producen durante el trabajo—, como económicos —si se tienen en cuenta los costes derivados de incapacidad temporal, pérdida en horas de trabajo o por disminución de productividad—. La constante evolución en este ámbito implica que la vigilancia de la salud de los trabajadores expuestos a este riesgo debe adaptarse al conocimiento y la evidencia más actual. Objetivo: El objetivo de nuestra revisión es estructurar y analizar la literatura más reciente sobre el tema para determinar qué efectos sobre la salud se asocian al uso habitual de las pantallas de visualización de datos.Método: Durante los meses de noviembre 2015 a enero de 2016 se efectuó una búsqueda bibliográfica utilizando combinaciones de las palabras clave «eyestrain», «occupational diseases», «video display terminals», «musculoskeletal diseases», «occupational diseases», «computer», «work» y «population surveillance» en las bases de datos electrónicas PubMed y la Cochrane Library, limitada a los últimos diez años. La población objeto del estudio en nuestra revisión son los individuos expuestos a PVD y los resultados, en términos de salud, los síntomas o patologías que se relacionan con el uso de estas tecnologías. [ES] ntroduction: The changes in the world of work and the introduction of new technologies in recent years have led to an increasing use of visual display terminals (VDT) in many jobs. The discomfort and symptoms experienced during the use of VDT can have a significant impact in terms of quality, —as a result of the increase in the number of mistakes at work—, as well as the economic ones —taking into account the costs derived from temporary incapacity, the loss in working hours or the decrease of productivity—.The constant evolution in this area implies that the workers’ health surveillance exposed to this risk must be adapted to the knowledge and the most current evidence. Objective: The objective of our review is to structure and analyze the most recent literature on the subject to determine which health effects are associated with the usual use of visual display terminals. Method: Among November 2015 and January 2016 a bibliographic search was carried out using the keywords combinations «eyestrain», «occupational diseases», «video display terminals», «musculoskeletal diseases», «occupational diseases», «computer» «work» and population surveillance «in the electronic databases PubMed and the Cochrane Library limited to the last ten years. The studied population are individuals exposed to DDS and the results, in terms of health, symptoms or pathologies associated with the use of these technologies. Symptoms, diseases or disorders related to psychosocial risks were excluded of the search. The criteria for the selection of the articles were based on whether the study population had to be fully or partially employed and used computers or data visualization screens and that the health effects had to be in the visual or musculoskeletal sphere, related to working conditions or associated risk factors.Articles were not initially excluded because of language or type of study. The SIGN criteria (Scottish Intercollegiate Guidelines Network) were used to classify the scientific evidence and to determine the degree of the recommendations.N

Revisión sistemática sobre las alteraciones óculo-visuales y músculo-esqueléticas asociadas al trabajo con pantallas de visualización de datos

Resumen Introducción: Los cambios en el mundo del trabajo y la introducción de nuevas tecnologías en los últimos años han propiciado el aumento del uso de pantallas de visualización de datos (PVD) en multitud de puestos de trabajo. El malestar y los síntomas que se experimentan durante el uso de PVD pueden tener un impacto importante en términos de calidad, -derivado del aumento en el número de errores que se producen durante el trabajo-, como económicos -si se tienen en cuenta los costes derivados de incapacidad temporal, pérdida en horas de trabajo o por disminución de productividad-. La constante evolución en este ámbito implica que la vigilancia de la salud de los trabajadores expuestos a este riesgo debe adaptarse al conocimiento y la evidencia más actual. Objetivo: El objetivo de nuestra revisión es estructurar y analizar la literatura más reciente sobre el tema para determinar qué efectos sobre la salud se asocian al uso habitual de las pantallas de visualización de datos. Método: Durante los meses de noviembre 2015 a enero de 2016 se efectuó una búsqueda bibliográfica utilizando combinaciones de las palabras clave «eyestrain», «occupational diseases», «video display terminals», «musculoskeletal diseases», «occupational diseases», «computer», «work» y «population surveillance» en las bases de datos electrónicas PubMed y la Cochrane Library, limitada a los últimos diez años. La población objeto del estudio en nuestra revisión son los individuos expuestos a PVD y los resultados, en términos de salud, los síntomas o patologías que se relacionan con el uso de estas tecnologías. Se han excluido de la búsqueda de síntomas, enfermedades o trastornos relacionados con los riesgos psicosociales. Los criterios para la selección de los artículos se basaron en que la población de estudio debía ser trabajadora, total o parcialmente, que utilizara ordenadores o pantallas de visualización de datos y que los efectos para la salud debían ser en la esfera óculo-visual o musculo-esquelética, relacionada con las condiciones de trabajo o factores de riesgo asociados. No se excluyeron inicialmente artículos por motivo de idioma o tipo de estudio. Para clasificar la evidencia científica y determinar el grado de las recomendaciones se utilizaron los criterios del SIGN (Scottish Intercollegiate Guidelines Network). Resultados: Resultado de la búsqueda inicial se localizaron 1711 referencias, de las cuáles, una vez leídos los títulos y excluidos los duplicados, se redujeron a 496. Una vez leído los resúmenes se excluyeron otras 424 referencias al considerar que el contenido no era relevante y por motivos idiomáticos. De los restantes 72 artículos, se excluyeron otros 10 bien porque el contenido no se consideró relevante o no respondía a los criterios de inclusión, de modo que finalmente se incluyeron 62 artículos en la revisión final. Los trabajadores usuarios de PVD habitualmente presentan síntomas de malestar y dolor relacionados con el trabajo. Actualmente existen datos que sugieren relación entre el uso de estos equipos y problemas a nivel de la zona cervical. En menor medida, también se asocia con sintomatología de muñeca-mano y con la vergencia y el astigmatismo a nivel óculo-visual. Conclusiones: La inclusión de sintomatología en la mayor parte de estudios (recogida a través de cuestionarios), hace más complicada la valoración de patología asociada al uso de PVD. En general es factible identificar molestias o síntomas subjetivos, pero es difícil traducirlo en patologías concretas si no son debidamente contrastadas con pruebas objetivas y bien definidas. Aunque no existen recomendaciones sólidas para efectuar intervenciones específicas en el lugar de trabajo, una estrategia de intervenciones múltiples se apunta como el enfoque más razonable, priorizando actividades de prevención primaria y secundaria, promoviendo el correcto diseño de los lugares de trabajo y actuando sobre la capacitación de los trabajadores para que ellos mismos se conviertan en sujetos activos de la prevención. Son precisos más estudios, con diseños longitudinales y con carácter multicéntrico para poder generar mayor evidencia entre la asociación de problemas osteomusculares y óculo-visuales con la exposición laboral a PVD