Exhaustive Search of Ligand Binding Pathways via Volume-based Metadynamics

Determining the complete set of ligands' binding/unbinding pathways is important for drug discovery and to rationally interpret mutation data. Here we have developed a metadynamics-based technique that addressed this issue and allows estimating affinities in the presence of multiple escape pathways. Our approach is shown on a Lysozyme T4 variant in complex with the benzene molecule. The calculated binding free energy is in agreement with experimental data. Remarkably, not only we were able to find all the previously identified ligand binding pathways, but also we uncovered 3 new ones. This results were obtained at a small computational cost, making this approach valuable for practical applications, such as screening of small compounds libraries

Exact value for the average optimal cost of bipartite traveling-salesman and 2-factor problems in two dimensions

We show that the average cost for the traveling-salesman problem in two dimensions, which is the archetypal problem in combinatorial optimization, in the bipartite case, is simply related to the average cost of the assignment problem with the same Euclidean, increasing, convex weights. In this way we extend a result already known in one dimension where exact solutions are avalaible. The recently determined average cost for the assignment when the cost function is the square of the distance between the points provides therefore an exact prediction $$\overline{E_N} = \frac{1}{\pi}\, \log N$$ for large number of points $2N$. As a byproduct of our analysis also the loop covering problem has the same optimal average cost. We also explain why this result cannot be extended at higher dimensions. We numerically check the exact predictions.Comment: 5 pages, 3 figure

An implementation of the maximum-caliber principle by replica-averaged time-resolved restrained simulations

Inferential methods can be used to integrate experimental informations and molecular simulations. The maximum entropy principle provides a framework for using equilibrium experimental data and it has been shown that replica-averaged simulations, restrained using a static potential, are a practical and powerful implementation of such principle. Here we show that replica-averaged simulations restrained using a time-dependent potential are equivalent to the principle of maximum caliber, the dynamic version of the principle of maximum entropy, and thus may allow to integrate time-resolved data in molecular dynamics simulations. We provide an analytical proof of the equivalence as well as a computational validation making use of simple models and synthetic data. Some limitations and possible solutions are also discussed

Coevolutionary data-based interaction networks approach highlighting key residues across protein families: The case of the G-protein coupled receptors

We present an approach that, by integrating structural data with Direct Coupling Analysis, is able to pinpoint most of the interaction hotspots (i.e. key residues for the biological activity) across very sparse protein families in a single run. An application to the Class A G-protein coupled receptors (GPCRs), both in their active and inactive states, demonstrates the predictive power of our approach. The latter can be easily extended to any other kind of protein family, where it is expected to highlight most key sites involved in their functional activity

A Data-Driven Dimensionality Reduction Approach to Compare and Classify Lipid Force Fields

Molecular dynamics simulations of all-atom and coarse-grained lipid bilayer models are increasingly used to obtain useful insights for understanding the structural dynamics of these assemblies. In this context, one crucial point concerns the comparison of the performance and accuracy of classical force fields (FFs), which sometimes remains elusive. To date, the assessments performed on different classical potentials are mostly based on the comparison with experimental observables, which typically regard average properties. However, local differences of the structure and dynamics, which are poorly captured by average measurements, can make a difference, but these are nontrivial to catch. Here, we propose an agnostic way to compare different FFs at different resolutions (atomistic, united-atom, and coarse-grained), by means of a high-dimensional similarity metrics built on the framework of Smooth Overlap of Atomic Position (SOAP). We compare and classify a set of 13 FFs, modeling 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. Our SOAP kernel-based metrics allows us to compare, discriminate, and correlate different FFs at different model resolutions in an unbiased, high-dimensional way. This also captures differences between FFs in modeling nonaverage events (originating from local transitions), for example, the liquid-to-gel phase transition in dipalmitoylphosphatidylcholine (DPPC) bilayers, for which our metrics allows us to identify nucleation centers for the phase transition, highlighting some intrinsic resolution limitations in implicit versus explicit solvent FFs

Biological compatibility between two temperate lineages of brown dog ticks, Rhipicephalus sanguineus (sensu lato)

Background: The brown dog tick Rhipicephalus sanguineus (sensu stricto) is reputed to be the most widespread tick of domestic dogs worldwide and has also been implicated in the transmission of many pathogens to dogs and humans. For more than two centuries, Rh. sanguineus (s.s.) was regarded as a single taxon, even considering its poor original description and the inexistence of a type specimen. However, genetic and crossbreeding experiments have indicated the existence of at least two distinct taxa within this name: the so-called "temperate" and "tropical" lineages of Rh. sanguineus (sensu lato). Recent genetic studies have also demonstrated the existence of additional lineages of Rh. sanguineus (s.l.) in Europe and Asia. Herein, we assessed the biological compatibility between two lineages of Rh. sanguineus (s.l.) found in southern Europe, namely Rhipicephalus sp. I (from Italy) and Rhipicephalus sp. II (from Portugal). Methods: Ticks morphologically identified as Rh. sanguineus (s.l.) were collected in southern Portugal and southern Italy. Tick colonies were established and crossbreeding experiments conducted. Morphological, biological and genetic analyses were conducted. Results: Crossbreeding experiments confirmed that ticks from the two studied lineages were able to mate and generate fertile hybrids. Hybrid adult ticks always presented the same genotype of the mother, confirming maternal inheritance of mtDNA. However, larvae and nymphs originated from Rhipicephalus sp. I females presented mtDNA genotype of either Rhipicephalus sp. I or Rhipicephalus sp. II, suggesting the occurrence of paternal inheritance or mitochondrial heteroplasmy. While biologically compatible, these lineages are distinct genetically and phenotypically. Conclusions: The temperate lineages of Rh. sanguineus (s.l.) studied herein are biologically compatible and genetic data obtained from both pure and hybrid lines indicate the occurrence of paternal inheritance or mitochondrial heteroplasmy. This study opens new research avenues and raises question regarding the usefulness of genetic data and crossbreeding experiments as criteria for the definition of cryptic species in ticks

A bearing fault model for Independent Cart Conveyor System and its validation

Independent Cart Conveyor System is one of the most promising technology in automation industries. It combines the benefits of servo motors with the advantages of linear motors. It consists of a close path made up of modular linear motors having a curved or a straight shape that control a fleet of carts independently. Each cart is placed along the motors and it is connected, through rolling bearings, to a rail set on the motors themselves. The bearings are subject to wear and the condition monitoring of these elements is challenging for the non-stationary working conditions of variable load and variable speed profiles. This paper provides a bearing fault vibration model that takes into account the mechanical design of the cart, its motion profile, the shape of the conveyor path, the load variation and the type of fault on the rolling bearing

Resting Energy Expenditure in Anorexia Nervosa: Measured versus Estimated

Introduction. Aim of this study was to compare the resting energy expenditure (REE) measured by the Douglas bag method with the REE estimated with the FitMate method, the Harris-Benedict equation, and the Müller et al. equation for individuals with BMI < 18.5 kg/m2 in a severe group of underweight patients with anorexia nervosa (AN). Methods. 15 subjects with AN participated in the study. The Douglas bag method and the FitMate method were used to measure REE and the dual energy X-ray absorptiometry to assess body composition after one day of refeeding. Results. FitMate method and the Müller et al. equation gave an accurate REE estimation, while the Harris-Benedict equation overestimated the REE when compared with the Douglas bag method. Conclusion. The data support the use of the FitMate method and the Müller et al. equation, but not the Harris-Benedict equation, to estimate REE in AN patients after short-term refeeding