Locuaz: an in silico platform for protein binders optimization.

MOTIVATION: Engineering high-affinity binders targeting specific antigenic determinants remains a challenging and often daunting task, requiring extensive experimental screening. Computational methods have the potential to accelerate this process, reducing costs and time, but only if they demonstrate broad applicability and efficiency in exploring mutations, evaluating affinity, and pruning unproductive mutation paths. RESULTS: In response to these challenges, we introduce a new computational platform for optimizing protein binders towards their targets. The platform is organized as a series of modules, performing mutation selection and application, molecular dynamics simulations to sample conformations around interaction poses, and mutation prioritization using suitable scoring functions. Notably, the platform supports parallel exploration of different mutation streams, enabling in silico high-throughput screening on High Performance Computing (HPC) systems. Furthermore, the platform is highly customizable, allowing users to implement their own protocols. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/pgbarletta/locuaz and documentation is at https://locuaz.readthedocs.io/. The data underlying this article are available at https://github.com/pgbarletta/suppl_info_locuaz.

In-depth theoretical understanding of the chemical interaction of aromatic compounds with a gold nanoparticle.

Gold Nanoparticles (GNPs), owing to their unique properties and versatile preparation strategy, have been demonstrated to exhibit promising applications in diverse fields, which include bio-sensors, catalysts, nanomedicines and radiotherapy. Yet, the nature of the interfacial interaction of GNPs with their chemical environment remains elusive. Experimental vibrational spectroscopy can reveal different interactions of aromatic biological molecules absorbed on GNPs, that may result from changes in the orientation of the molecule. However, the presence of multiple functional groups and the aqueous solvent introduces competition, and complexifies the spectral interpretations. Therefore, our objective is to theoretically investigate the adsorption of aromatic molecules containing various functional groups on the surface of GNPs to comparatively study their preferred adsorption modes. The interaction between Au32, as a model of GNPs, and a series of substituted aromatic compounds that includes benzene, aniline, phenol, toluene, benzoic acid, acetophenone, methyl benzoate, and thiophenol, is investigated. Our computed interaction energies highlight the preference of the aromatic ring to lie flat on the surface. The orientations of the molecules can be distinguished using infrared spectroscopy along with strong changes in intensity and significant shifts of some vibrational modes when the molecule interacts with the GNP. The interaction energy and the electron transfer between the nanoparticle and the aromatic molecule are not found to correlate, possibly because of significant back donation of electrons from GNPs to organic molecules as revealed by charge decomposition analysis. A thorough quantum topological analysis identifies multiple non-covalent interactions and assigns the nature of the interaction mostly to dative interactions between the aromatic ring and the GNP as well as dispersive interaction. Finally, energy decomposition analyses point out the role of the charge transfer energy contribution in the subtle balance of the different physical components.

Probing the structural properties of the water solvation shell around gold nanoparticles: A computational study.

While subjected to radiation, gold nanoparticles (GNPs) have been shown to enhance the production of radicals when added to aqueous solutions. It has been proposed that the arrangement of water solvation layers near the water-gold interface plays a significant role. As such, the structural and electronic properties of the first water solvation layer surrounding GNPs of varying sizes were compared to bulk water using classical molecular dynamics and quantum and semi-empirical methods. Classical molecular dynamics was used to understand the change in macroscopic properties of bulk water in the presence of different sizes of GNP, as well as by including salt ions. The analysis of these macroscopic properties has led to the conclusion that larger GNPs induce the rearrangement of water molecules to form a 2D hydrogen-bond network at the interface. Quantum methods were employed to understand the electronic nature of the interaction between water molecules and GNPs along with the change in the water orientation and the vibrational density of states. The stretching region of vibrational density of states was found to extend into the higher wavenumber region, as the size of the GNP increases. This extension represents the dangling water molecules at the interface, as a result of reorientation of the water molecules in the first solvation shell. This multi-level study suggests that in the presence of GNP of increasing sizes, the first water solvation shell undergoes a rearrangement to maximize the water-water interactions as well as the water-GNP interactions.

Graphene-Oxide-Catalyzed Direct CH-CH-Type Cross-Coupling: The Intrinsic Catalytic Activities of Zigzag Edges.

The development of graphene oxide (GO)-based materials for C-C cross-coupling represents a significant advance in carbocatalysis. Although GO has been used widely in various catalytic reactions, the scope of reactions reported is quite narrow, and the relationships between the type of functional groups present and the specific activity of the GO are not well understood. Herein, we explore CH-CH-type cross-coupling of xanthenes with arenes using GO as real carbocatalysts, and not as stoichiometric reactants. Mechanistic studies involving molecular analogues, as well as trapped intermediates, were carried out to probe the active sites, which were traced to quinone-type functionalities as well as the zigzag edges in GO materials. GO-catalyzed cross-dehydrogenative coupling is operationally simple, shows reusability over multiple cycles, can be conducted in air, and exhibits good functional group tolerance.

Tandem catalysis of amines using porous graphene oxide.

Porous graphene oxide can be used as a metal-free catalyst in the presence of air for oxidative coupling of primary amines. Herein, we explore a GO-catalyzed carbon-carbon or/and carbon-heteroatom bond formation strategy to functionalize primary amines in tandem to produce a series of valuable products, i.e., α-aminophosphonates, α-aminonitriles, and polycyclic heterocompounds. Furthermore, when decorated with nano-Pd, the Pd-coated porous graphene oxide can be used as a bifunctional catalyst for tandem oxidation and hydrogenation reactions in the N-alkylation of primary amines, achieving good to excellent yields under mild conditions.

A Step-by-Step Assembly of a 3D Coordination Polymer in the Solid-State by Desolvation and [2+2] Cycloaddition Reactions.

Two solid-state structural transformations that occur in a stepwise and a controlled manner are described. A combination of desolvation and cycloaddition reactions has been employed to synthesise a 3D coordination polymer (CP) from 1D CP [Cd(bdc)(4-spy)2 (H2 O)]⋅2 H2 O⋅2 DMF (bdc=1,4-benzenedicarboxylate, 4-spy=4-styrylpyridine) presumably via a 2D layered structure, [Cd2 (bdc)2 (4-spy)4 ]. In the absence of single crystals to follow the course of the photocycloaddition reaction, thermogravimetry, XAFS and NOESY NMR experiments were used to propose the formation of layered and pillared layered structures. Further, the present strategy enables us to synthesise new multidimensional architectures that are otherwise inaccessible by the self-assembly process.

Assembly of 3D coordination polymers from 2D sheets by [2+2] cycloaddition reaction.

The synthesis of three 2D interdigitated Zn(II) coordination polymers (CPs), by using three monotopic ligands containing C=C bonds, is reported. Among these, two CPs with 4spy (4-styryl pyridine) and 2F-4spy (a 2'-fluoro derivative of 4spy) ligands showed quantitative formation of cyclobutane rings, thus demonstrating a unique synthetic procedure to synthesize metal-organic frameworks (MOFs) by using this photochemical reaction. Interestingly, these compounds can also be synthesized by mechanochemical grinding procedures by using Zn(OAc)2. In contrast, Zn(NO3)2 did not yield the required product, unlike in the solution route. In addition, compounds with 4vpy (4-vinylpyridine), 4spy and 2F-4spy ligands created different units in the CPs; 4vpy and 2F-4spy furnished paddle wheel units, whereas 4spy yielded tetrahedral Zn(II) repeating units. Furthermore, the change in coordination geometry manifests in the photoluminescence properties, attributed to the difference in charge-transfer and ligand-centered fluorescent phenomenon.

Computational Mutagenesis of Antibody Fragments: Disentangling Side Chains from ΔΔG Predictions.

The development of highly potent antibodies and antibody fragments as binding agents holds significant implications in fields such as biosensing and biotherapeutics. Their binding strength is intricately linked to the arrangement and composition of residues at the binding interface. Computational techniques offer a robust means to predict the three-dimensional structure of these complexes and to assess the affinity changes resulting from mutations. Given the interdependence of structure and affinity prediction, our objective here is to disentangle their roles. We aim to evaluate independently six side-chain reconstruction methods and ten binding affinity estimation techniques. This evaluation was pivotal in predicting affinity alterations due to single mutations, a key step in computational affinity maturation protocols. Our analysis focuses on a data set comprising 27 distinct antibody/hen egg white lysozyme complexes, each with crystal structures and experimentally determined binding affinities. Using six different side-chain reconstruction methods, we transformed each structure into its corresponding mutant via in silico single-point mutations. Subsequently, these structures undergo minimization and molecular dynamics simulation. We therefore estimate ΔΔG values based on the original crystal structure, its energy-minimized form, and the ensuing molecular dynamics trajectories. Our research underscores the critical importance of selecting reliable side-chain reconstruction methods and conducting thorough molecular dynamics simulations to accurately predict the impact of mutations. In summary, our study demonstrates that the integration of conformational sampling and scoring is a potent approach to precisely characterizing mutation processes in single-point mutagenesis protocols and crucial for computational antibody design.

Use of Gaussian-Type Functions for Describing Fast Ion-Matter Irradiation with Time-Dependent Density Functional Theory.

The electronic stopping power is an observable property that quantifies the ability of swift ions to penetrate matter to transfer energy to the electron cloud. The recent literature has proven the value of Real-Time Time-Dependent Density Functional Theory to accurately evaluate this property from first-principles, but questions remain regarding the capability of computer codes relying on atom-centered basis functions to capture the physics at play. In this Perspective, we draw attention to the fact that irradiation by swift ions triggers electron emission into the continuum, especially at the Bragg peak. We investigate the ability of Gaussian atomic orbitals (AOC), which were fitted to mimic continuum wave functions, to improve electronic stopping power predictions. AOC are added to standard correlation-consistent basis sets or STO minimal basis sets. Our benchmarks for water irradiation by fast protons clearly advocate for the use of AOC, especially near the Bragg peak. We show that AOC only need to be placed on the molecules struck by the ion. The number of AOC that are added to the usual basis set is relatively small compared to the total number of atomic orbitals, making the use of such a basis set an excellent choice from a computational cost point of view. The optimum basis set combination is applied for the calculation of the stopping power of a proton in water with encouraging agreement with experimental data.

Highly Crystalline K-Intercalated Polymeric Carbon Nitride for Visible-Light Photocatalytic Alkenes and Alkynes Deuterations.

In addition to the significance of photocatalytic hydrogen evolution, the utilization of the in situ generated H/D (deuterium) active species from water splitting for artificial photosynthesis of high value-added chemicals is very attractive and promising. Herein, photocatalytic water splitting technology is utilized to generate D-active species (i.e., Dad) that can be stabilized on anchored 2nd metal catalyst and are readily for tandem controllable deuterations of carbon-carbon multibonds to produce high value-added D-labeled chemicals/pharmaceuticals. A highly crystalline K cations intercalated polymeric carbon nitride (KPCN), rationally designed, and fabricated by a solid-template induced growth, is served as an ultraefficient photocatalyst, which shows a greater than 18-fold enhancement in the photocatalytic hydrogen evolution over the bulk PCN. The photocatalytic in situ generated D-species by superior KPCN are utilized for selective deuteration of a variety of alkenes and alkynes by anchored 2nd catalyst, Pd nanoparticles, to produce the corresponding D-labeled chemicals and pharmaceuticals with high yields and D-incorporation. This work highlights the great potential of developing photocatalytic water splitting technology for artificial photosynthesis of value-added chemicals instead of H2 evolution.