The scientific potential and technological challenges of the High-Luminosity Large Hadron Collider program.

We present an overview of the High-Luminosity (HL-LHC) program at the Large Hadron Collider (LHC), its scientific potential and technological challenges for both the accelerator and detectors. The HL-LHC program is expected to start circa 2027 and aims to increase the integrated luminosity delivered by the LHC by an order of magnitude at the collision energy of 14 TeV. This requires upgrades to the injector system, accelerator complex and luminosity levelling.

Mixed Strong-Electroweak Corrections to the Drell-Yan Process.

We report on the first complete computation of the mixed QCD-electroweak (EW) corrections to the neutral-current Drell-Yan process. Superseding previously applied approximations, our calculation provides the first result at this order that is valid in the entire range of dilepton invariant masses. The two-loop virtual contribution is computed by using semianalytical techniques, overcoming the technical problems in the evaluation of the relevant master integrals.

Polymer Folding Simulations from Hi-C Data.

In the absence of a clear molecular understanding of the mechanism that stabilizes specific contacts in interphasic chromatin, we resort to the principle of maximum entropy to build a polymeric model based on the Hi-C data of the specific system one wants to study. The interactions are set by an iterative Monte Carlo algorithm to reproduce the average contacts summarized by the Hi-C map. The study of the ensemble of conformations generated by the algorithm can report a much richer set of information than the experimental map alone, including colocalization of multiple sites, fluctuations of the contacts, and kinetical properties.

Parton Density Uncertainties and the Determination of Electroweak Parameters at Hadron Colliders.

We discuss the determination of electroweak parameters from hadron collider observables, focusing on the W-boson mass measurement. We revise the procedures adopted in the literature to include in the experimental analysis the uncertainty due to our imperfect knowledge of the proton structure. We show how the treatment of the proton parton density functions' (PDFs') uncertainty as a source of systematic error leads to the automatic inclusion in the fit of the bin-bin correlation of the kinematic distributions with respect to PDF variations.

A Combined NMR-Computational Study of the Interaction between Influenza Virus Hemagglutinin and Sialic Derivatives from Human and Avian Receptors on the Surface of Transfected Cells.

The development of small-molecule inhibitors of influenza virus Hemagglutinin could be relevant to the opposition of the diffusion of new pandemic viruses. In this work, we made use of Nuclear Magnetic Resonance (NMR) spectroscopy to study the interaction between two derivatives of sialic acid, Neu5Ac-α-(2,6)-Gal-β-(1⁻4)-GlcNAc and Neu5Ac-α-(2,3)-Gal-β-(1⁻4)-GlcNAc, and hemagglutinin directly expressed on the surface of recombinant human cells. We analyzed the interaction of these trisaccharides with 293T cells transfected with the H5 and H1 variants of hemagglutinin, which thus retain their native trimeric conformation in such a realistic environment.

Cold Denaturation of the HIV-1 Protease Monomer.

The human immunodeficiency virus-1 (HIV-1) protease is a complex protein that in its active form adopts a homodimer dominated by β-sheet structures. We have discovered a cold-denatured state of the monomeric subunit of HIV-1 protease that is populated above 0 °C and therefore directly accessible to various spectroscopic approaches. Using nuclear magnetic resonance secondary chemical shifts, temperature coefficients, and protein dynamics, we suggest that the cold-denatured state populates a compact wet globule containing transient non-native-like α-helical elements.

The molecular evolution of HIV-1 protease simulated at atomic detail.

Progress in understanding protein folding allows to simulate, with atomic detail, the evolution of amino-acid sequences folding to a given native conformation. A particularly attractive example is the HIV-1 protease, main target of therapies to fight AIDS, which under drug pressure is able to develop resistance within few months from the starting of therapy. By comparing the results of simulations of the evolution of the protease with the corresponding proteomic data, one can approximately determine the value of the associated evolution pressure under which the enzyme has become and, as a consequence, map out the energy landscape in sequence space of the HIV-1 protease.

Identification and characterization of folding inhibitors of hen egg lysozyme: an example of a new paradigm of drug design.

Studies of protein folding indicate the presence of native contacts in the denatured state, giving rise to folding elements which contribute to the accomplishment of the native state. The possibility of finding molecules which can interact with specific folding elements of a target protein preventing it from reaching its native state, and hence from becoming biologically active, is particularly attractive. The notion that folding elements not only provide molecular recognition directing the folding process, but also have conserved sequence, implies that targeting such elements will make protein folding inhibitors less susceptible to mutations which, in many cases, abrogate drug effects.

Urea and guanidinium chloride denature protein L in different ways in molecular dynamics simulations.

In performing protein-denaturation experiments, it is common to employ different kinds of denaturants interchangeably. We make use of molecular dynamics simulations of Protein L in water, in urea, and in guanidinium chloride (GdmCl) to ascertain if there are any structural differences in the associated unfolding processes. The simulation of proteins in solutions of GdmCl is complicated by the large number of charges involved, making it difficult to set up a realistic force field.

HIV-1 protease folding and the design of drugs which do not create resistance.

Human immunodeficiency virus type 1 (HIV-1) protease (PR) plays an essential role in the life cycle of the virus. Consequently, its inhibition can control acquired immunodeficiency syndrome (AIDS). Any pharmacological treatment targeting the active site of the protease is known to generate escape mutants.

Denatured state is critical in determining the properties of model proteins designed on different folds.

The thermodynamics of proteins designed on three common folds (SH3, chymotrypsin inhibitor 2 [CI2], and protein G) is studied with a simplified C(alpha) model and compared with the thermodynamics of proteins designed on random-generated folds. The model allows to design sequences to fold within a dRMSD ranging from 1.2 to 4.

Oscillations and temporal signalling in cells.

The development of new techniques to quantitatively measure gene expression in cells has shed light on a number of systems that display oscillations in protein concentration. Here we review the different mechanisms which can produce oscillations in gene expression or protein concentration using a framework of simple mathematical models. We focus on three eukaryotic genetic regulatory networks which show 'ultradian' oscillations, with a time period of the order of hours, and involve, respectively, proteins important for development (Hes1), apoptosis (p53) and immune response (NF-kappaB).

Low-throughput model design of protein folding inhibitors.

The stabilization energy of proteins in their native conformation is not distributed uniformly among all the amino acids, but is concentrated in few (short) fragments, fragments which play a key role in the folding process and in the stability of the protein. Peptides displaying the same sequence as these key fragments can compete with the formation of the most important native contacts, destabilizing the protein and thus inhibiting its biological activity. We present an essentially automatic method to individuate such peptidic inhibitors based on a low-throughput screening of the fragments which build the target protein.

Thermodynamic features characterizing good and bad folding sequences obtained using a simplified off-lattice protein model.

The thermodynamics of the small SH3 protein domain is studied by means of a simplified model where each beadlike amino acid interacts with the others through a contact potential controlled by a random matrix. Good folding sequences, characterized by a low native energy, display three main thermodynamical ensembles, namely, a coil-like ensemble, an unfolded globule, and a folded ensemble (plus two other states, frozen and random coils, populated only at extreme temperatures). Interestingly, the unfolded globule has some regions already structured.

Sequence of events in folding mechanism: beyond the Gō model.

Simplified Gō models, where only native contacts interact favorably, have proven useful to characterize some aspects of the folding of small proteins. The success of these models is limited by the fact that all residues interact in the same way so that the folding features of a protein are determined only by the geometry of its native conformation. We present an extended version of a Calpha-based Gō model where different residues interact with different energies.