Investigating the competition between ACE2 natural molecular interactors and SARS-CoV-2 candidate inhibitors

: The SARS-CoV-2 pandemic still poses a threat to the global health as the virus continues spreading in most countries. Therefore, the identification of molecules capable of inhibiting the binding between the ACE2 receptor and the SARS-CoV-2 spike protein is of paramount importance. Recently, two DNA aptamers were designed with the aim to inhibit the interaction between the ACE2 receptor and the spike protein of SARS-CoV-2. Indeed, the two molecules interact with the ACE2 receptor in the region around the K353 residue, preventing its binding of the spike protein. If on the one hand this inhibition process hinders the entry of the virus into the host cell, it could lead to a series of side effects, both in physiological and pathological conditions, preventing the correct functioning of the ACE2 receptor. Here, we discuss through a computational study the possible effect of these two very promising DNA aptamers, investigating all possible interactions between ACE2 and its experimentally known molecular partners. Our in silico predictions show that some of the 10 known molecular partners of ACE2 could interact, physiologically or pathologically, in a region adjacent to the K353 residue. Thus, the curative action of the proposed DNA aptamers could recruit ACE2 from its biological functions

Dynamical changes of SARS-CoV-2 spike variants in the highly immunogenic regions impact the viral antibodies escaping

The prolonged circulation of the SARS-CoV-2 virus resulted in the emergence of several viral variants, with different spreading features. Moreover, the increased number of recovered and/or vaccinated people introduced a selective pressure toward variants able to evade the immune system, developed against the former viral versions. This process results in reinfections. Aiming to study the latter process, we first collected a large structural dataset of antibodies in complex with the original version of SARS-CoV-2 Spike protein. We characterized the peculiarities of such antibodies population with respect to a control dataset of antibody-protein complexes, highlighting some statistically significant differences between these two sets of antibodies. Thus, moving our attention to the Spike side of the complexes, we identify the Spike region most prone to interaction with antibodies, describing in detail also the energetic mechanisms used by antibodies to recognize different epitopes. In this framework, fast protocols able to assess the effect of novel mutations on the cohort of developed antibodies would help establish the impact of the variants on the population. Performing a molecular dynamics simulation of the trimeric form of the SARS-CoV-2 Spike protein for the wild type and two variants of concern, that is, the Delta and Omicron variants, we described the physicochemical features and the conformational changes experienced locally by the variants with respect to the original version. Hence, combining the dynamical information with the structural study on the antibody-spike dataset, we quantitatively explain why the Omicron variant has a higher capability of escaping the immune system than the Delta variant, due to the higher conformational variability of the most immunogenic regions. Overall, our results shed light on the molecular mechanism behind the different responses the SARS-CoV-2 variants display against the immune response induced by either vaccines or previous infections. Moreover, our analysis proposes an approach that can be easily extended to both other SARS-CoV-2 variants or different molecular systems

2D Zernike polynomial expansion: finding the protein-protein binding regions

We present a method for efficiently and effectively assessing whether and where two proteins can interact with each other to form a complex. This is still largely an open problem, even for those relatively few cases where the 3D structure of both proteins is known. In fact, even if much of the information about the interaction is encoded in the chemical and geometric features of the structures, the set of possible contact patches and of their relative orientations are too large to be computationally affordable in a reasonable time, thus preventing the compilation of reliable interactome. Our method is able to rapidly and quantitatively measure the geometrical shape complementarity between interacting proteins, comparing their molecular iso-electron density surfaces expanding the surface patches in term of 2D Zernike polynomials. We first test the method against the real binding region of a large dataset of known protein complexes, reaching a success rate of 0.72. We then apply the method for the blind recognition of binding sites, identifying the real region of interaction in about 60% of the analyzed cases. Finally, we investigate how the efficiency in finding the right binding region depends on the surface roughness as a function of the expansion order

Simulation and modelling of transient electric fields in hvdc insulation systems based on polarization current measurements

Simulating and modelling electric field dynamics in the insulation of medium-and high-voltage DC electrical systems is needed to support insulation design optimization and to evaluate the impact of voltage transients on ageing mechanisms and insulation reliability. In order to perform accurate simulations, appropriate physical models must be adopted for the insulating material properties, particularly conductivity, which drives the electric field in a steady-state condition and contributes to determining the field behavior during voltage and load transients. In order to model insulation conductivity, polarization, and conduction, mechanisms must be inferred through charging and discharging current measurements, generally performed at different values of electric field and temperatures in flat specimens of the material under study. In general, both mechanisms are present, but one of them may be predominant with respect to the other depending on type of material. In this paper, we showed that models based on predominant polarization mechanisms were suitable to describe impregnated paper, but not polymers used for HV and MV DC insulation. In the latter case, indeed, trapping–detrapping and conduction phenomena were predominant compared to polarization, thus conductivity models had to be considered, in addition to or as a replacement of the polarization model, in order to carry out proper electric field simulations

Flexible platform with wireless interface for DC-motor remote control

Several portable applications, such as small electric vehicles and power tools, often require the use of direct current (DC) motors that significantly differ from one to another in terms of power, torque, and driving techniques. New market requirements of these applications suggest the implementation of smart user interfaces that may allow the introduction of those devices in the new Internet of Things paradigm by making them connected. This paper discusses the design and verification of a flexible platform able to drive different types of DC motors that is also provided with a Bluetooth connection for remote control and monitoring. As the platform can drive different motors with different driving techniques, it provides standardisation and cost reduction in the production of a set of tools. Two gardening tools are used as case study to verify the design and flexibility of the board. Both tools are successfully controlled and monitored with a wireless connected remote user interface

Implementation of the fast charging concept for electric local public transport: The case-study of a minibus

This paper shows an effective implementation of the fast charging concept in the electric local public transport context. An electric minibus powered with a lead-acid battery is considered as a case-study. Its traction battery is redesigned using 12 V standard lithium-iron-phosphate modules to benefit from the higher performance of the lithium battery technology compared to the lead-acid one. The minibus can achieve a continuous operation characterised by 20 min of traveling alternated with 10 min of standstill for fast recharging of the battery. Experiments performed on a single module of the battery show that the load profile is sustained without appreciable issues both in temperature and life degradation of the lithium cells

A novel strategy for molecular interfaces optimization: the case of ferritin-transferrin receptor interaction

Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the ad hoc design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces

Experimental Analysis of an Electric Minibus with Small Battery and Fast Charge Policy

The lead-acid battery of an electric minibus has been replaced with a smaller size lithium-ion battery system consisting of standard 12 V modules and a hierarchical battery management system. The minibus has experimentally been tested to show that the reduced battery capacity, which also cuts costs, does not affect the daily operational mission. This is assuming that the driving phases are alternated with fast charging periods. Experiments show that fast charging of 8 min guarantees up to 1 h of operation

Dietary determinants of postprandial blood glucose control in adults with type 1 diabetes on a hybrid closed-loop system

Aims/hypothesis: The aim of this work was to assess the relationship between meal nutrients and postprandial blood glucose response (PGR) in individuals with type 1 diabetes on a hybrid closed-loop system (HCLS). Methods: The dietary composition of 1264 meals (398 breakfasts, 441 lunches and 425 dinners) was assessed by 7-day food records completed by 25 individuals with type 1 diabetes on HCLSs (12 men/13 women, mean ± SD age 40 ± 12 years, mean ± SD HbA1c 51 ± 10 mmol/mol [6.9 ± 0.2%]). For each meal, PGR (continuous glucose monitoring metrics, glucose incremental AUCs) and insulin doses (pre-meal boluses, post-meal microboluses automatically delivered by the pump and adjustment boluses) over 6 h were evaluated. Results: Breakfast, lunch and dinner significantly differed with respect to energy and nutrient intake and insulin doses. The blood glucose postprandial profile showed an earlier peak after breakfast and a slow increase until 4 h after lunch and dinner (p < 0.001). Mean ± SD postprandial time in range (TIR) was better at breakfast (79.3 ± 22.2%) than at lunch (71.3 ± 23.9%) or dinner (70.0 ± 25.9%) (p < 0.001). Significant negative predictors of TIR at breakfast were total energy intake, per cent intake of total protein and monounsaturated fatty acids, glycaemic load and absolute amounts of cholesterol, carbohydrates and simple sugars consumed (p < 0.05 for all). No significant predictors were detected for TIR at lunch. For TIR at dinner, a significant positive predictor was the per cent intake of plant proteins, while negative predictors were glycaemic load and intake amounts of simple sugars and carbohydrate (p < 0.05 for all). Conclusions/interpretation: This study shows that nutritional factors other than the amount of carbohydrate significantly influence postprandial blood glucose control. These nutritional determinants vary between breakfast, lunch and dinner, with differing effects on postprandial blood glucose profile and insulin requirements, thus remaining a challenge to HCLSs. Graphical abstract: [Figure not available: see fulltext.]