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Nanometer-sized clusters are often targeted due to their potential applications as nanoreactors or storage/delivery devices. One route to assemble and stabilize finite structures consists of imparting directional bonding patterns between the nanoparticles. When only a portion of the particle surface is able to form an inter-particle bond, finite-size aggregates such as micelles and vesicles may form. Building on this approach, we combine particle shape anisotropy with the directionality of the bonding patterns and investigate the combined effect of particle elongation and surface patchiness on the low density assembly scenario. To this aim, we study the assembly of tip-functionalised Janus hard spherocylinders by means of Monte Carlo simulations. By exploring the effects of changing the interaction strength and range at different packing fractions, we highlight the role played by shape and bond anisotropy on the emerging aggregates (micelles, vesicles, elongated micelles, and lamellae). We observe that shape anisotropy plays a crucial role in suppressing phases that are typical to spherical Janus nanoparticles and that a careful tuning of the interaction parameters allows promoting the formation of spherical micelles. These finite-size spherical clusters composed of elongated particles might offer more interstitials and larger surface areas than those offered by micelles of spherical or almost-spherical units, thus enhancing their storage and catalytic properties.

HSP70 and its evolutionarily diverged co-chaperone HSP110, forms an important node in protein folding cascade. How these proteins maintain the aggregation-prone proteome of malaria parasite in functional state remains underexplored, in contrast to its human orthologs. In this study, we have probed into conformational dynamics of plasmodial HSP70 and HSP110 through multiple μs MD-simulations (ATP-state) and compared with their respective human counterparts. Simulations covered sampling of 3.4 and 2.8 μs for HSP70 and HSP110, respectively, for parasite and human orthologs. We provide a comprehensive description of the dynamic behaviors that characterize the systems and also introduce a parameter for quantifying protein rigidity. For HSP70, the interspecies comparison reveals enhanced flexibility in IA and IB subdomain within the conserved NBD, lesser solvent accessibility of the interdomain linker and distinct dynamics of the SBDβ of Pf HSP70 in comparison to Hs HSP70. In the case of HSP110, notable contrast in the dynamics of NBD, SBDβ and SBDα was observed between parasite and human ortholog. Although HSP70 and HSP110 are members of the same superfamily, we identified specific differences in the subdomain contacts in NBD, linker properties and interdomain movements in their human and parasite orthologs. Our study suggests that differences in conformational dynamics may translate into species-specific differences in the chaperoning activities of HSP70-HSP110 in the parasite and human, respectively. Dynamical features of Pf HSP70-HSP110 may contribute to the maintenance of proteostasis in the parasite during its intracellular survival in the host., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The design of nano-functionalised membranes or channels, able to effectively adsorb pollutants in aqueous solutions, is a topic that is gaining a great deal of attention in the materials science community. With this work we explore, through a combination of scaling theories and molecular dynamics simulations, the adsorption of spherical non-deformable colloidal nanoparticles within planar polymeric brushes. Our strategy is twofold: first, we generalise the Alexander-de Gennes theory for planar homopolymeric brushes to the case of diblock copolymer brushes, then we map the adsorbing homopolymeric brushes onto a diblock copolymer system, where the adsorbed colloids and all interacting monomers are considered monomers in bad solvent and we apply the generalised scaling theory to this effective diblock copolymer. This allows the prediction of the average conformation of the grafted substrate, i.e. its average height, as a function of the amount of loaded particles, as well as the introduction of a continuous mapping between a homopolymeric brush, the fraction of loaded particles and the average height of the adsorbing substrate., Competing Interests: None., (This journal is © The Royal Society of Chemistry.)

The rich and complex phase diagram typical of anisotropic biological or synthetic nanoparticles, has brought a great deal of interest over the equilibrium phase behaviour of non-spherical colloids. Amongst the class of anisotropic nanoparticles, hard spherocylindrical colloids have been, over the years, extensively studied because of their optical properties, for their rich phase diagrams, and their important industrial applications, as model particles for biological systems (viruses), or for example as potential drug carriers having the ability of surviving the attacks of the immune systems. As real anisotropic nanoparticles are often polydisperse in size and/or in shape, unveiling the effect of such a perturbation over their equilibrium phase diagram is of paramount importance. This work focuses on the effects of polydispersity over the full equilibrium phase diagram of hard spherocylindrical colloids (HSCs). Previous studies showed that a polydispersity in L alters the equilibrium phase diagram of HSCs. With this work we determine, both theoretically as well as computationally, the effects due to a generic polydispersity, namely in D , in L and, in both ones, on the equilibrium phase diagram and introduce a viable theoretical generalisation of the Onsager theory that allows us to get some insight into the observed phase behaviour.

Unveiling a general law for adsorption within macromolecules sets an important step forward in the design of nanomaterials with tunable and controllable properties. Reaching such a generalised control would have an important outcome in a plethora of possible fields, from biomedical applications up to materials science. In fact, the definition of classes regrouping adsorbing macromolecules with different geometrical or chemical properties would enormously simplify the design of controllable adsorbing materials, especially when geometrical or chemical constraints are set by the particular application. In this work we derive, through a combination of Scaling Theories and Molecular Dynamics Simulations, a general law for adsorption of spherical non-deformable colloidal nanoparticles within polymeric macromolecules of different geometries. Starting from the case of adsorption of a single colloid within macromolecular systems, we extend the results to the case in which finite adsorption takes place. We then derive simple predictions linking the adsorption potential to general properties of classes of macromolecules, and introduce a set of measurable quantities that can be exploited as an indirect measurement for loading.

Inhibition of the SARS-CoV-2 main protease (M pro ) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M pro . Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC 50 values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein-inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for M pro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Multiscale QM/MM approaches have become the most suitable and effective methods for the investigation of spectroscopic properties of medium- or large-size chromophores in condensed phases. On these grounds, we are developing a novel workflow aimed at improving the generality, reliability, and ease of use of the available tools. In the present paper, we report the latest developments of such an approach with specific reference to a general workplan starting with the addition of acetonitrile to the panel of solvents already available in the General Liquid Optimized Boundary (GLOB) model enforcing nonperiodic boundary conditions (NPBC). Next, the solvatochromic shifts induced by acetonitrile on both rigid (uracil and thymine) and flexible (thyrosine) chromophores have been studied introducing in our software a number of new features ranging from rigid-geometry NPBC molecular dynamics based on the quaternion formalism to a full integration of variational (ONIOM) and perturbative (perturbed matrix method (PMM)) approaches for describing different solute-solvent topologies and local fluctuations, respectively. Finally, thymine and uracil have been studied also in methanol to point out the generality of the computational strategy. While further developments are surely needed, the strengths of our integrated approach even in its present version are demonstrated by the accuracy of the results obtained by an unsupervised approach and coupled to a computational cost strongly reduced with respect to that of conventional QM/MM models without any appreciable accuracy deterioration.

We extend a recently proposed computational strategy for the simulation of absorption spectra of semi-rigid molecular systems in condensed phases to the emission spectra of flexible chromophores. As a case study, we have chosen the CPL spectrum of camphor in methanol solution, which shows a well-defined bisignate shape. The first step of our approach is the quantum mechanical computation of reference spectra including vibrational averaging effects and taking bulk solvent effects into account by means of the polarizable continuum model. In the present case, the large amplitude inversion mode is explicitly treated by a numerical approach, whereas the other small-amplitude vibrational modes are taken into account within the harmonic approximation. Next, the snapshots of classical molecular dynamics computations are clusterized and one representative configuration from each cluster is used to compute a reference spectrum. In the present case, different clusters correspond to the two stable conformers of camphor in the S1 excited electronic state and, for each of them, to different numbers of strong solute-solvent hydrogen bonds. Finally, local fluctuation effects within each cluster are taken into account by means of the perturbed matrix model. The overall procedure leads to good agreement with experiment for absorption and emission spectra together with their chiral counterparts, thus allowing to analyze the role of different effects (stereo-electronic, vibrational, environmental) in tuning the overall experimental spectra., (Copyright © 2020 Del Galdo, Fusè and Barone.)

This paper deals with the development and first validation of a composite approach for the simulation of chiroptical spectra in solution aimed to strongly reduce the number of full QM computations without any significant accuracy loss. The approach starts from the quantum mechanical computation of reference spectra including vibrational averaging effects and taking average solvent effects into account by means of the polarizable continuum model. Next, the snapshots of classical molecular dynamics computations are clusterized and one reference configuration from each cluster is used to compute a reference spectrum. Local fluctuation effects within each cluster are then taken into account by means of the perturbed matrix model. The performance of the proposed approach is tested on the challenging case of the optical and chiroptical spectra of camphorquinone in methanol solution. Although further validations are surely needed, the results of this first study are quite promising also taking into account that agreement with experimental data is reached by just a couple of full quantum mechanical geometry optimizations and frequency computations.

Here we present a theoretical-computational study of the thermodynamics and kinetics of an aqueous Trp-cage, a 20-residue long miniprotein. The combined use of accurate molecular dynamics simulations rigorously reconstructing the proper isobar of the system and a sound statistical-mechanical model provides a quantitative description of the temperature dependence of the relevant physical-chemical properties and insights into the detailed mechanisms regulating the folding-unfolding properties.

The search for stationary points in the molecular potential energy surfaces (PES) is a problem of increasing relevance in different fields of molecular sciences especially for large, flexible systems characterized by several large-amplitude internal motions leading to shallow minima with comparable energies and separated by small barriers. After structural biology and medicinal chemistry, also high-resolution molecular spectroscopy, which is the focus of our research activity, is nowadays shifting its attention to this kind of molecular systems. In such circumstances, accurate geometrical structures and relative stabilities of all these minima are a mandatory prerequisite for the vis-à-vis comparison between computed and experimental spectra. This task raises, in turn, the problem of the best compromise between accuracy and feasibility. In our opinion, a promising route is offered by a two-level stochastic search in which a relatively inexpensive MM or QM method is used in the initial search, followed by single point energy evaluation at a higher QM level of a relatively large number of low-energy structures in order to select a final short-list of candidates, whose geometries are fully optimized at the higher QM level. Finally, the relative stabilities and properties of the final short-list of energy minima can be computed by a state-of-the-art QM approach. This strategy defines a general two-level search/three-level evaluation approach, which can be finely tuned in terms of the accuracy of the sought results. Setup of the procedure, interface with a general purpose electronic structure code and validation of the most effective low-level methods for some representative molecular systems (three already well characterized and one new) ended up with a general, robust and user-friendly tool, which can be easily used and extended also by non-specialists to aid experimental spectroscopic studies.

Antifreeze proteins (AFPs) have the ability to inhibit ice growth by binding to ice nuclei. Their ice-binding mechanism is still unclear, yet the hydration layer is thought to play a fundamental role. Here, we use molecular dynamics simulations to characterize the hydration shell of two AFPs and two non-AFPs. The calculated shell thickness and density of the AFPs do not feature any relevant difference with respect to the non-AFPs. Moreover, the hydration shell density is always higher than the bulk density and, thus, no low-density, ice-like layer is detected at the ice-binding surface (IBS) of AFPs. Instead, we observe local water-density differences in AFPs between the IBS (lower density) and the non-IBS (higher density). The lower solvent density at the ice-binding site can pave the way to the protein binding to ice nuclei, while the higher solvent density at the non-ice-binding surfaces might provide protection against ice growth.

In this article, we investigated the structural and dynamical evolutionary behaviour of a set of ten thioredoxin proteins as formed by three extant forms and seven resurrected ones in laboratory. Starting from the crystallographic structures, we performed all-atom molecular dynamics simulations and compare the trajectories in terms of structural and dynamical properties. Interestingly, the structural properties related to the protein density (i.e. the number of residues divided by the excluded molecular volume) well describe the protein evolutionary behaviour. Our results also suggest that the changes in sequence as occurred during the evolution have affected the protein essential motions, allowing us to discriminate between ancient and extant proteins in terms of their dynamical behaviour. Such results are yet more evident when the bacterial, archaeal and eukaryotic thioredoxins are separately analysed.

Computational simulation of UV/vis spectra in condensed phases can be performed starting from converged molecular dynamics (MD) simulations and then performing quantum mechanical/molecular mechanical (QM/MM) computations for a statistically significant number of snapshots. However, the need of variational solutions (e.g., ONIOM/EE) for a huge number of snapshots makes unpractical the use of state-of-the-art QM Hamiltonians. On the other hand, the effectivity of perturbative approaches (e.g., perturbed matrix method, PMM) comes at the price of poor convergence for configurations strongly different from the reference one. In this paper we introduce an integrated strategy based on a cluster analysis of the MD snapshots. Next, a representative configuration for each cluster is treated at the ONIOM/EE level, whereas local fluctuations within each cluster are described at the PMM level. Some representative systems (uracil in dimethylformamide and in water and tyrosine zwitterion in water) are analyzed to show the effectivity and flexibility of the proposed strategy.

Background: The mechanism of how the hydrophilic threefold channel (C3) of ferritin nanocages facilitates diffusion of diverse metal ions into the internal cavity remains poorly explored., Methods: Computational modeling and free energy estimations were carried out on R. catesbeiana H´ ferritin. Transit features and associated energetics for Fe 2+ , Mg 2+ , Zn 2+ ions through the C3 channel have been examined., Results: We highlight that iron conduction requires the involvement of two Fe 2+ ions in the channel. In such doubly occupied configuration, as observed in X-ray structures, Fe 2+ is displaced from the internal site (stabilized by D127) at lower energetic cost. Moreover, comparison of Fe 2+ , Mg 2+ and Zn 2+ transit features shows that E130 geometric constriction provides not only an electrostatic anchor to the incoming ions but also differentially influence their diffusion kinetics., Conclusions: Overall, the study provides insights into Fe 2+ entry mechanism and characteristic features of metal-protein interactions that influence the metal ions passage. The dynamics data suggest that E130 may act as a metal selectivity gate. This implicates an ion-specific entry mechanism through the channel with the distinct diffusion kinetics being the discriminating factor., General Significance: Ferritin nanocages not only act as biological iron reservoirs but also have gained importance in material science as template scaffolds for synthesizing metal nanoparticles. This study provides mechanistic understanding on the conduction of different metal ions through the channel., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Some years ago we developed a theoretical-computational hybrid quantum/classical methodology, the Perturbed Matrix Method (PMM), to be used in conjunction with molecular dynamics simulations for the investigation of chemical processes in complex systems, that proved to be a valuable tool for the simulation of relevant experimental observables, e.g., spectroscopic signals, reduction potentials, kinetic constants. In typical PMM calculations the quantum sub-part of the system, the quantum centre, is embedded into an external perturbing field providing a perturbation operator explicitly calculated up to the dipolar terms. In this paper we further develop the PMM approach, beyond the dipolar terms in the perturbation operator expansion, by including explicitly the quadrupolar terms and/or by expanding the perturbation operator on each atom of the quantum centre. These different levels of the perturbation operator expansion, providing different levels of theory, have been tested by calculating three different spectroscopic observables: the spectral signal of liquid water and aqueous benzene due to the lowest energy electronic excitation and the infrared amide I band of aqueous trans-N-methylacetamide. All the systems tested show that, even though the previous PMM level of theory is already capable of reproducing the main features of the spectral signal, the higher levels of theory improve the quantitative reproduction of the spectral details.

Despite an intense interest and a remarkable number of studies on the subject, the relationships between thermostability and (primary, secondary and tertiary) structure of proteins are still not fully understood. Here, comparing the protein density - defined by the ratio between the residue number and protein excluded volume - for a set of thermophilic/mesophilic pairs, we provide evidence that this property is connected to the optimal growth temperature. In particular, our results indicate that thermophilic proteins have - in general - a lower density with respect to the mesophilic counterparts, being such a correlation more pronounced for optimal growth temperature differences greater than 40°C. The effect of the protein thermostability changes on the molecular shape is also presented.

The UV-vis spectrum of Tyrosine and its response to different backbone protonation states have been studied by applying the Perturbed Matrix Method (PMM) in conjunction with molecular dynamics (MD) simulations. Herein, we theoretically reproduce the UV-vis absorption spectrum of aqueous solution of Tyrosine in its zwitterionic, anionic and cationic forms, as well as of aqua-p-Cresol (i.e., the moiety that constitutes the side chain portion of Tyrosine). To achieve a better accuracy in the MD sampling, the Tyrosine Force Field (FF) parameters were derived de novo via quantum mechanical calculations. The UV-vis absorption spectra are computed considering the occurring electronic transitions in the vertical approximation for each of the chromophore configurations sampled by the classical MD simulations, thus including the effects of the chromophore semiclassical structural fluctuations. Finally, the explicit treatment of the perturbing effect of the embedding environment permits to fully model the inhomogeneous bandwidth of the electronic spectra. Comparison between our theoretical-computational results and experimental data shows that the used model captures the essential features of the spectroscopic process, thus allowing to perform further analysis on the strict relationship between the quantum properties of the chromophore and the different embedding environments. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Computational modeling involving Quantum Mechanics (QM) and Molecular Mechanics (MM) calculations are widely utilized to unveil the atomic-molecular properties that underpin their inherent characteristic features. The choice over the either of the QM and MM methods or a multiscale composite approach is driven by the target property of interest, and of course, the molecular size. Often, tailor-made schemes need to be devised to match the specific study purpose. Herein, we provide a perspective of these approaches addressing their effectiveness in terms of the delicate balance between the accuracy and computational feasibility. We focus on representative examples to highlight how different approaches can be fruitfully exploited for modeling the conformational landscape, and possibly, the spectroscopic behavior of biochemical molecules, especially amino acids building blocks., (© 2018 Wiley Periodicals, Inc.)

The Perturbed Matrix Method (PMM) approach to be used in combination with Molecular Dynamics (MD) trajectories (MD-PMM) has been recoded from scratch, improved in several aspects, and implemented in the Gaussian suite of programs for allowing a user-friendly and yet flexible tool to estimate quantum chemistry observables in complex systems in condensed phases. Particular attention has been devoted to a description of rigid and flexible quantum centers together with powerful essential dynamics and clustering approaches. The default implementation is fully black-box and does not require any external action concerning both MD and PMM sections. At the same time, fine-tuning of different parameters and use of external data are allowed in all the steps of the procedure. Two specific systems (Tyrosine and Uridine) have been reinvestigated with the new version of the code in order to validate the implementation, check the performances, and illustrate some new features.

In this paper we apply the computational analysis recently proposed by our group to characterize the solvation properties of a native protein in aqueous solution, and to four model aqueous solutions of globular proteins in their unfolded states thus characterizing the protein unfolded state hydration shell and quantitatively evaluating the protein unfolded state partial molar volumes. Moreover, by using both the native and unfolded protein partial molar volumes, we obtain the corresponding variations (unfolding partial molar volumes) to be compared with the available experimental estimates. We also reconstruct the temperature and pressure dependence of the unfolding partial molar volume of Myoglobin dissecting the structural and hydration effects involved in the process.

In this paper we present a computational approach, based on NVT molecular dynamics trajectories, that allows the direct evaluation of the protein partial molecular volume. The results obtained for five different globular proteins demonstrate the accuracy of this computational procedure in reproducing protein partial molecular volumes, providing quantitative characterization of the hydration shell in terms of the protein excluded volume, hydration shell ellipsoidal volume and related solvent density. Remarkably, our data indicate for the hydration shell a ≈10% solvent density increase with respect to the liquid water bulk density, in excellent agreement with the available experimental data.