Replacement names for three preoccupied genus-group names of Cetoniinae (Coleoptera: Scarabaeidae).

The names of three genus-level taxa of Cetoniinae from Southeast Asia are reviewed. Aurelia Thomson, 1880, currently a subgenus of Ixorida Thomson, 1880, is preoccupied by Aurelia Lamarck, 1816, and Emas Allsopp, Jákl & Rey, new replacement name, is proposed. This results in Ixorida (Emas) decorata Antoine, 1986, Ixorida (Emas) gloriosa Jákl, 2014, Ixorida (Emas) kaorui Jákl, 2019, Ixorida (Emas) philippei Sakai & Nagai, 1998, and Ixorida (Emas) thoracica (Wallace, 1867). Legrandia Jákl, 2019, currently a subgenus of Ruteraetia Krikken, 1980, is preoccupied by Legrandia Beddome, 1883, and Legrandetia Allsopp, Jákl & Rey, new replacement name is proposed, resulting in Ruteraetia (Legrandetia) pahangensis Jákl, 2019. Sternoplus Wallace, 1867 is preoccupied by Sternoplus Mulsant & Rey, 1864, and Walsternoplus Allsopp, Jákl & Rey, new replacement name is proposed, resulting in Walsternoplus schaumii (White, 1856), new combination, and Walsternoplus chicheryi (Antoine, 1999), new combination.

A Note on the Effects of Linear Topology Preservation in Monte Carlo Simulations of Knotted Proteins.

Monte Carlo simulations are a powerful technique and are widely used in different fields. When applied to complex molecular systems with long chains, such as those in synthetic polymers and proteins, they have the advantage of providing a fast and computationally efficient way to sample equilibrium ensembles and calculate thermodynamic and structural properties under desired conditions. Conformational Monte Carlo techniques employ a move set to perform the transitions in the simulation Markov chain. While accepted conformations must preserve the sequential bonding of the protein chain model and excluded volume among its units, the moves themselves may take the chain across itself. We call this a break in linear topology preservation. In this manuscript, we show, using simple protein models, that there is no difference in equilibrium properties calculated with a move set that preserves linear topology and one that does not. However, for complex structures, such as those of deeply knotted proteins, the preservation of linear topology provides correct equilibrium results but only after long relaxation. In any case, to analyze folding pathways, knotting mechanisms and folding kinetics, the preservation of linear topology may be an unavoidable requirement.

Colorectal cancer: comparative analysis between two series of patients separated by more than three decades

Abstract Aim This study characterizes Colorectal Cancer (CRC) incidence in the University Hospital Ramon and Cajal, Madrid, and analyzes variations over time. It establishes risk groups, aiming to discover whether diagnosis can be determined in less advanced stages of disease. Method Evolutionary epidemiological study of genetic and environmental factors contributing to the development of CRC in this district that enables the comparison of two cohorts of patients separated by 37 years: G1 (patients of current group) and G2 (patients of historical group). The main risk variables gleaned retrospectively were analyzed and the statistical association between cohorts was determined. Results The mean age of patients increased significantly from 64 to 71 along with the incidence of ascending colon cancer. G1 scored higher than G2 for: the incidence of colon cancer in men, detection of adenomatous polyps (48.1%), percentage of resectability with curative intent (80.4%), and Dukes A stage (34.1%) (p < 0.001). Conclusion Biological aspects of CRC have been compared against its profile three decades earlier. We can confirm the existence of concrete changes in the manifestation and staging at the time of diagnosis or following earlier treatment. (AU)

Behavior of Proteins under Pressure from Experimental Pressure-Dependent Structures.

Structure-based models are coarse-grained representations of the interactions responsible for the protein folding process. In their simplest form, they use only the native contact map of a given protein to predict the main features of its folding process by computer simulation. Given their limitations, these models are frequently complemented with sequence-dependent contributions or additional information. Specifically, to analyze the effect of pressure on the folding/unfolding transition, special forms of these interaction potentials are employed, which may a priori determine the outcome of the simulations. In this work, we have tried to keep the original simplicity of structure-based models. Therefore, we have used folded structures that have been experimentally determined at different pressures to define native contact maps and thus interactions dependent on pressure. Despite the apparently tiny structural differences induced by pressure, our simulation results provide different thermodynamic and kinetic behaviors, which roughly correspond to experimental observations (when there is a possible comparison) of two proteins used as benchmarks, hen egg-white lysozyme and dihydrofolate reductase. Therefore, this work shows the feasibility of using experimental native structures at different pressures to analyze the global effects of this physical property on the protein folding process.

Self-Consistent Mean Field Calculations of Polyelectrolyte-Surfactant Mixtures in Solution and upon Adsorption onto Negatively Charged Surfaces.

Self-Consistent Mean-Field Calculations (SCF) have provided a semi-quantitative description of the physico-chemical behavior of six different polyelectrolyte-surfactant mixtures. The SCF calculations performed showed that both the formation of polymer-surfactant in bulk and the adsorption of the formed complexes onto negatively-charged surfaces are strongly affected by the specific nature of the considered systems, with the polymer-surfactant interactions playing a central role in the self-assembly of the complexes that, in turn, affects their adsorption onto interfaces and surfaces. This work evidences that SCF calculations are a valuable tool for deepening on the understanding of the complex physico-chemical behavior of polyelectrolyte-surfactant mixtures. However, it is worth noting that the framework obtained on the basis of an SCF approach considered an equilibrium situation which may, in some cases, be far from the real situation appearing in polyelectrolyte-surfactant systems.

Hydrophobic confinement modulates thermal stability and assists knotting in the folding of tangled proteins.

There is growing support for the idea that the in vivo folding process of knotted proteins is assisted by chaperonins, but the mechanism of chaperonin assisted folding remains elusive. Here, we conduct extensive Monte Carlo simulations of lattice and off-lattice models to explore the effects of confinement and hydrophobic intermolecular interactions with the chaperonin cage in the folding and knotting processes. We find that moderate to high protein-cavity interactions (which are likely to be established in the beginning of the chaperonin working cycle) cause an energetic destabilization of the protein that overcomes the entropic stabilization driven by excluded volume, and leads to a decrease of the melting temperature relative to bulk conditions. Moreover, mild-to-moderate hydrophobic interactions with the cavity (which would be established later in the cycle) lead to a significant enhancement of knotting probability in relation to bulk conditions while simultaneously moderating the effect of steric confinement in the enhancement of thermal stability. Our results thus indicate that the chaperonin may be able to assist knotting without simultaneously thermally stabilizing potential misfolded states to a point that would hamper productive folding thus compromising its functional role.

Design of a structure-based model for protein folding from flexible conformations.

The use of coarse-grained models is important in many fields, especially those that use computer simulation to analyze large systems in processes that span long-time scales, as happens in protein folding. Among those approaches, structure-based models have been widely and successfully used for a few decades now. They usually take a single native conformation, experimentally solved, of the protein studied to determine the native contacts, which subsequently define the interaction potential for the simulation. The characteristics of the folding transition can then be analyzed from the computed trajectories. In this paper, we consider the possibility of enriching these models by considering the structural fluctuations present in the native state of a globular protein at room temperature in an aqueous environment. We use the different conformers experimentally provided when the protein structure was determined by nuclear magnetic resonance (NMR) spectroscopy as an approximate ensemble to test our methodology, which includes the definition of a global interaction potential and the analysis of the thermodynamic and structural characteristics of the folding process. The results are compared with traditional, single structure models.

Steric confinement and enhanced local flexibility assist knotting in simple models of protein folding.

The chaperonin complex GroEL-GroES is able to accelerate the folding process of knotted proteins considerably. However, the folding mechanism inside the chaperonin cage is elusive. Here we use a combination of lattice and off-lattice Monte Carlo simulations of simple Go models to study the effect of physical confinement and local flexibility on the folding process of protein model systems embedding a trefoil knot in their native structure. This study predicts that steric confinement plays a specific role in the folding of knotted proteins by increasing the knotting probability for very high degrees of confinement. This effect is observed for protein MJ0366 even above the melting temperature for confinement sizes compatible with the size of the GroEL/GroES chaperonin cage. An enhanced local flexibility produces the same qualitative effects on the folding process. In particular, we observe that knotting probability increases up to 40% in the transition state of protein MJ0366 when flexibility is enhanced. This is underlined by a structural change in the transition state, which becomes devoid of helical content. No relation between the knotting mechanism and flexibility was found in the context of the off-lattice model adopted in this work.

How determinant is N-terminal to C-terminal coupling for protein folding?

This work investigates the role of N- to C- termini coupling in the folding transition of small, single domain proteins via extensive Monte Carlo simulations of both lattice and off-lattice models. The reported results provide compelling evidence that the existence of native interactions between the terminal regions of the polypeptide chain (i.e. termini coupling) is a major determinant of the height of the free energy barrier that separates the folded from the denatured state in a two-state folding transition, therefore being a critical modulator of protein folding rates and thermodynamic cooperativity. We further report that termini interactions are able to substantially modify the kinetic behavior dictated by the full set of native interactions. Indeed, a native structure of high contact order with "switched-off" termini-interactions actually folds faster than its circular permutant of lowest CO.

Intermediates in the folding equilibrium of repeat proteins from the TPR family.

In recent decades, advances in computational methods and experimental biophysical techniques have improved our understanding of protein folding. Although some of these advances have been remarkable, the structural variability of globular proteins usually encountered makes it difficult to extract general features of their folding processes. To overcome this difficulty, experimental and computational studies of the folding of repeat (or modular) proteins are of interest. Because their native structures can be described as linear arrays of the same, repeated, supersecondary structure unit, it is possible to seek a possibly independent behavior of the different modules without taking into account the intrinsic stability associated with different secondary structure motifs. In this work we have used a Monte Carlo-based simulation to study the folding equilibrium of four repeat proteins belonging to the tetratricopeptide repeat family. Our studies provide new insights into their energy profiles, enabling investigation about the existence of intermediate states and their relative stabilities. We have also performed structural analyses to describe the structure of these intermediates, going through the vast number of conformations obtained from the simulations. In this way, we have tried to identify the regions of each protein in which the modular structure yields a different behavior and, more specifically, regions of the proteins that can stay folded when the rest of the chain has been thermally denatured.

Design of a rotamer library for coarse-grained models in protein-folding simulations.

Rotamer libraries usually contain geometric information to trace an amino acid side chain, atom by atom, onto a protein backbone. These libraries have been widely used in protein design, structure refinement and prediction, homology modeling, and X-ray and NMR structure validation. However, they usually present too much information and are not always fully compatible with the coarse-grained models of the protein geometry that are frequently used to tackle the protein-folding problem through molecular simulation. In this work, we introduce a new backbone-dependent rotamer library for side chains compatible with low-resolution models in polypeptide chains. We have dispensed with an atomic description of proteins, representing each amino acid side chain by its geometric center (or centroid). The resulting rotamers have been estimated from a statistical analysis of a large structural database consisting of high-resolution X-ray protein structures. As additional information, each rotamer includes the frequency with which it has been found during the statistical analysis. More importantly, the library has been designed with a careful control to ensure that the vast majority of side chains in protein structures (at least 95% of residues) are properly represented. We have tested our library using an independent set of proteins, and our results support a good correlation between the reconstructed centroids from our rotamer library and those in the experimental structures. This new library can serve to improve the definition of side chain centroids in coarse-grained models, avoiding at the same time an excessive additional complexity in a geometric model for the polypeptide chain.

Sketching protein aggregation with a physics-based toy model.

We explore the applicability of a single-bead coarse-grained molecular model to describe the competition between protein folding and aggregation. We have designed very simple and regular sequences, based on our previous studies on peptide aggregation, that successfully fold into the three main protein structural families (all-α, all-ß, and α + ß). Thanks to equilibrium computer simulations, we evaluate how temperature and concentration promote aggregation. Aggregates have been obtained for all the amino acid sequences considered, showing that this process is common to all proteins, as previously stated. However, each structural family presents particular characteristics that can be related to its specific balance between hydrogen bond and hydrophobic interactions. The model is very simple and has limitations, yet it is able to reproduce both the cooperative folding of isolated polypeptide chains with regular sequences and the formation of different types of aggregates at high concentrations.

Simulating protein unfolding under pressure with a coarse-grained model.

We describe and test a coarse-grained molecular model for the simulation of the effects of pressure on the folding/unfolding transition of proteins. The model is a structure-based one, which takes into account the desolvation barrier for the formation of the native contacts. The pressure is taken into account in a qualitative, mean field approach, acting on the parameters describing the native stabilizing interactions. The model has been tested by simulating the thermodynamic and structural behavior of protein GB1 with a parallel tempering Monte Carlo algorithm. At low effective pressures, the model reproduces the standard two-state thermal transition between the native and denatured states. However, at large pressures a new state appears. Its structural characteristics have been analyzed, showing that it corresponds to a swollen version of the native structure. This swollen state is at equilibrium with the native state at low temperatures, but gradually transforms into the thermally denatured state as temperature is increased. Therefore, our model predicts a downhill transition between the swollen and the denatured states. The analysis of the model permits us to obtain a phase diagram for the pressure-temperature behavior of the simulated system, which is compatible with the known elliptical shape of this diagram for real proteins.

Simple model for the simulation of peptide folding and aggregation with different sequences.

We present a coarse-grained interaction potential that, using just one single interaction bead per amino acid and only realistic interactions, can reproduce the most representative features of peptide folding. We combine a simple hydrogen bond potential, recently developed in our group, with a reduced alphabet for the amino acid sequence, which takes into account hydrophobic interactions. The sequence does not pose any additional influence in the torsional properties of the chain, as it often appears in previously published work. Our model is studied in equilibrium simulations at different temperatures and concentrations. At low concentrations the effect of hydrophobic interactions is determinant, as α-helices (isolated or in bundles) or ß-sheets are the most populated conformations, depending on the simulated sequence. On the other hand, an increase in concentration translates into a higher influence of the hydrogen bond interactions, which mostly favor the formation of ß-type aggregates, in agreement with experimental observations. These aggregates, however, still keep some distinct characteristics for different sequences.

Why do protein folding rates correlate with metrics of native topology?

For almost 15 years, the experimental correlation between protein folding rates and the contact order parameter has been under scrutiny. Here, we use a simple simulation model combined with a native-centric interaction potential to investigate the physical roots of this empirical observation. We simulate a large set of circular permutants, thus eliminating dependencies of the folding rate on other protein properties (e.g. stability). We show that the rate-contact order correlation is a consequence of the fact that, in high contact order structures, the contact order of the transition state ensemble closely mirrors the contact order of the native state. This happens because, in these structures, the native topology is represented in the transition state through the formation of a network of tertiary interactions that are distinctively long-ranged.

Improvement of structure-based potentials for protein folding by native and nonnative hydrogen bonds.

Pure Go models (where every native interaction equally stabilizes the folded state) have widely proved their convenience in the computational investigation of protein folding. However, a chemistry-based description of the real interactions also provides a desirable tune in the analysis of the folding process, and thus some hybrid Go potentials that combine both aspects have been proposed. Among all the noncovalent interactions that contribute to protein folding, hydrogen bonds are the only ones with a partial covalent character. This feature makes them directional and, thus, more difficult to model as part of the coarse-grained descriptions that are typically employed in Go models. Thanks to a simplified but rigorous representation of backbone hydrogen bonds that we have recently proposed, we present in this article a combined potential (Go + backbone hydrogen bond) to study the thermodynamics of protein folding in the frame of very simple simulation models. We show that the explicit inclusion of hydrogen bonds leads to a systematic improvement in the description of protein folding. We discuss a representative set of examples (from two-state folders to downhill proteins, with different types of native structures) that reveal a relevant agreement with experimental data.

The protein folding transition state: insights from kinetics and thermodynamics.

We perform extensive lattice Monte Carlo simulations of protein folding to construct and compare the equilibrium and the kinetic transition state ensembles of a model protein that folds to the native state with two-state kinetics. The kinetic definition of the transition state is based on the folding probability analysis method, and therefore on the selection of conformations with 0.4

A refined hydrogen bond potential for flexible protein models.

One of the major disadvantages of coarse-grained hydrogen bond potentials, for their use in protein folding simulations, is the appearance of abnormal structures when these potentials are used in flexible chain models, and no other geometrical restrictions or energetic contributions are defined into the system. We have efficiently overcome this problem, for chains of adequate size in a relevant temperature range, with a refined coarse-grained hydrogen bond potential. With it, we have been able to obtain nativelike alpha-helices and beta-sheets in peptidic systems, and successfully reproduced the competition between the populations of these secondary structure elements by the effect of temperature and concentration changes. In this manuscript we detail the design of the interaction potential and thoroughly examine its applicability in energetic and structural terms, considering factors such as chain length, concentration, and temperature.

A simple simulation model can reproduce the thermodynamic folding intermediate of apoflavodoxin.

Flavodoxins are single domain proteins with an alpha/beta structure, whose function and folding have been well studied. Detailed experiments have shown that several members of this protein family present a stable intermediate, which accumulates along the folding process. In this work, we use a coarse-grained model for protein folding, whose interactions are based on the topology of the native state, to analyze the thermodynamic characteristics of the folding of Anabaena apoflavodoxin. Our model shows evidence for the existence of a thermodynamic folding intermediate, which reaches a significant population along the thermal transition. According to our simulation results, the intermediate is compact, well packed, and involves distortions of the native structure similar to those experimentally found. These mainly affect the long loop in the protein surface comprising residues 120-139. Although the agreement between simulation and experiment is not perfect, something impossible for a crude model, our results show that the topology of the native state is able to dictate a folding process which includes the presence of an intermediate for this protein.