Distinct conformational properties determined by implicit and explicit representation of protein-solvent interactions. An analytical and computer simulation study

In the protein folding problem, solvent-mediated forces are commonly represented by intra-chain pairwise contact energy. Although this approximation has proven to be useful in several circumstances, it is limited in some other aspects of the problem. Here we show that it is possible to achieve two models to represent the chain-solvent system. one of them with implicit and other with explicit solvent, such that both reproduce the same thermodynamic results. Firstly, lattice models treated by analytical methods, were used to show that the implicit and explicitly representation of solvent effects can be energetically equivalent only if local solvent properties are time and spatially invariant. Following, applying the same reasoning Used for the lattice models, two inter-consistent Monte Carlo off-lattice models for implicit and explicit solvent are constructed, being that now in the latter the solvent properties are allowed to fluctuate. Then, it is shown that the chain configurational evolution as well as the globule equilibrium conformation are significantly distinct for implicit and explicit solvent systems. Actually, strongly contrasting with the implicit solvent version, the explicit solvent model predicts: (i) a malleable globule, in agreement with the estimated large protein-volume fluctuations; (ii) thermal conformational stability, resembling the conformational hear resistance of globular proteins, in which radii of gyration are practically insensitive to thermal effects over a relatively wide range of temperatures; and (iii) smaller radii of gyration at higher temperatures, indicating that the chain conformational entropy in the unfolded state is significantly smaller than that estimated from random coil configurations. Finally, we comment on the meaning of these results with respect to the understanding of the folding process. (C) 2009 Elsevier B.V. All rights reserved.

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson`s disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

Can exocentric direction be dissociated from its exocentric distance in virtual environments?

We conducted two psychophysical experiments to investigate the relationship between processing mechanisms for exocentric distance and direction. In the first experiment, the task was to discriminate exocentric distances. In the second one, the task was to discriminate exocentric directions. The individual effects of distance and direction on each task were dissociated by analyzing their corresponding psychophysical functions. Under stereoscopicviewing conditions, distancejudgments of excentric intervals were not affected by exocentric direction. However, directionjudgments were influenced by the distance between the pair of stimuli. Therefore, the mechanism processing exocentric direction is dependent on exocentric distance, but the mechanism processing exocentric distance does not require exocentric: direction measures. As a result, we suggest that exocentric distance and direction are hierarchically processed, with distance preceding direction. Alternatively, and more probably, a necessary condition for processing the exocentric direction between two stimuli may be to know the location of each of them.

Application of a wrist dosimeter prototype for radiation monitoring ((153)Sm) during a therapeutic procedure simulation

Gamma and beta radiation emitting radiopharmaceuticals are handled in nuclear medicine services, and in many cases there is only individual monitoring of gamma radiation. In this paper, the results obtained using a wrist dosimeter prototype (CaSO(4):Dy + Teflon pellets) show that the doses for workers occupationally exposed to beta radiation from (153)Sm are not negligible. It is important that this dose is evaluated, and it has to be taken into consideration in the individual monitoring system.

Bioinformatics construction of the human cell surfaceome

Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.

A university extension course in leprosy: telemedicine in the Amazon for primary healthcare

There is a high prevalence of leprosy in the Amazon region of Brazil. We have developed a distance education course in leprosy for training staff of the Family Health Teams (FHTs). The course was made available through a web portal. Tele-educational resources were mediated by professors and coordinators, and included the use of theoretical content available through the web, discussion lists, Internet chat, activity diaries, 3-D video animations (Virtual Human on Leprosy), classes in video streaming and case simulation. Sixty-five FHT staff members were enrolled. All of them completed the course and 47 participants received a certificate at the end of the course. At the end of the course, 48 course-evaluation questionnaires were answered. A total of 47 participants (98%) considered the course as excellent. The results demonstrate the feasibility of an interactive, tele-education model as an educational resource for staff in isolated regions. Improvements in diagnostic skills should increase diagnostic suspicion of leprosy and may contribute to early detection.

Construction and Validation of the Brazilian Questionario de Respostas Socialmente Habilidosas Segundo Relato de Professores (QRSH-PR)

Behavioral problems in preschool children are one of the most frequent motives for seeking psychological care by parents and caregivers. Instruments are considered necessary, created from a Social Skills Training theoretical-practical perspective, which may systematically assist the identification of social skills and behavioral deficits. helping professionals in the prevention and/or reduction of behavioral problems. The purpose of this study was to test the psychometric validity and reliability of an instrument for evaluation of Socially Skilled Responses. from a teacher`s perspective (QRSH-PR). For this purpose, 260 preschool children were evaluated. differentiated in subgroups without and without behavioral difficulties, based on the Child Behavior Scale (Escala de Comportamento Infantil/ECI-Professor). Studies were conducted for construct. discrimination. concurrent and predictive validity. The Cronbach Alpha was calculated to evaluate internal consistency. The obtained results pointed to positive indicators in reference to construct, discrimination, and predictive validity, and even for good internal consistency. indicating that the items consistently measure the construct of social skills, and differentiated children with and without behavioral problems. The questionnaire is considered to be gauged for evaluation of socially skilled responses from preschool children. and applicable in educational and clinical environments.

Thermal/mechanical simulation and laboratory fatigue testing of an alternative yttria tetragonal zirconia polycrystal core-veneer all-ceramic layered crown design

This study evaluated the stress levels at the core layer and the veneer layer of zirconia crowns (comprising an alternative core design vs. a standard core design) under mechanical/thermal simulation, and subjected simulated models to laboratory mouth-motion fatigue. The dimensions of a mandibular first molar were imported into computer-aided design (CAD) software and a tooth preparation was modeled. A crown was designed using the space between the original tooth and the prepared tooth. The alternative core presented an additional lingual shoulder that lowered the veneer bulk of the cusps. Finite element analyses evaluated the residual maximum principal stresses fields at the core and veneer of both designs under loading and when cooled from 900 degrees C to 25 degrees C. Crowns were fabricated and mouth-motion fatigued, generating master Weibull curves and reliability data. Thermal modeling showed low residual stress fields throughout the bulk of the cusps for both groups. Mechanical simulation depicted a shift in stress levels to the core of the alternative design compared with the standard design. Significantly higher reliability was found for the alternative core. Regardless of the alternative configuration, thermal and mechanical computer simulations showed stress in the alternative core design comparable and higher to that of the standard configuration, respectively. Such a mechanical scenario probably led to the higher reliability of the alternative design under fatigue.