De novo design of potent and selective mimics of IL-2 and IL-15.

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor ßγc heterodimer (IL-2Rßγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rßγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rßγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

De novo design of a fluorescence-activating ß-barrel.

The regular arrangements of ß-strands around a central axis in ß-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with ß-barrels. Here we show that accurate de novo design of ß-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of ß-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli, yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures.

Acetonitrile real gas phase behavior from quasi-ideal gas to nanodroplets: A microscopical view.

We have applied a recently developed general purpose acetonitrile force field based on first-principles calculations to simulate acetonitrile in the gas phase at different temperatures and densities. These conditions range from nearly ideal to real gas phase behavior and condensation. The molecular dynamics simulation results agree fairly well with the experimental studies available in the literature on the gas samples. The structural analysis of aggregates and their associated interaction energies is examined and related to the early model proposed on molecular association and equilibrium determining the non-ideal behavior. The formation of dimers is mainly responsible for the non-ideal behavior of the gas at very low density, confirming suggested models based on previous experimental studies. However, when the density of the sample rises, the level of aggregation increases and the simple concept of dimerization does not hold anymore. The real behavior adopted by the gas is related to the distribution of molecular structures observed. The macroscopical view of a real gas as a generic interparticle interaction system without a defined form may then be rationalized on the basis of a defined molecular association originated by a distribution of aggregates at the low density regime. The sample with the highest density (∼1.4 × 103 mol m-3) at the lowest temperature exhibits a massive aggregation where most of the acetonitrile (ACN) molecules in the simulation box form a big cluster. Its radial distribution function is similar to that of the liquid ACN. This strongly inhomogeneous distribution in the box can be considered a condensation in the gas phase under specific density-T conditions. This formation opens the door to the potential tuning of its solvent properties as a function of its size in these nanodroplets that in turn are controlled by the density-T conditions.

Toward a realistic theoretical electronic spectra of metal aqua ions in solution: The case of Ce(H2O)n3+ using statistical methods and quantum chemistry calculations.

Accurately predicting spectra for heavy elements, often open-shell systems, is a significant challenge typically addressed using a single cluster approach with a fixed coordination number. Developing a realistic model that accounts for temperature effects, variable coordination numbers, and interprets experimental data is even more demanding due to the strong solute-solvent interactions present in solutions of heavy metal cations. This study addresses these challenges by combining multiple methodologies to accurately predict realistic spectra for highly charged metal cations in aqueous media, with a focus on the electronic absorption spectrum of Ce3+ in water. Utilizing highly correlated relativistic quantum mechanical (QM) wavefunctions and structures from molecular dynamics (MD) simulations, we show that the convolution of individual vertical transitions yields excellent agreement with experimental results without the introduction of empirical broadening. Good results are obtained for both the normalized spectrum and that of absolute intensity. The study incorporates a statistical machine learning algorithm, Gaussian Mixture Models-Nuclear Ensemble Approach (GMM-NEA), to convolute individual spectra. The microscopic distribution provided by MD simulations allows us to examine the contributions of the octa- and ennea-hydrate of Ce3+ in water to the final spectrum. In addition, the temperature dependence of the spectrum is theoretically captured by observing the changing population of these hydrate forms with temperature. We also explore an alternative method for obtaining statistically representative structures in a less demanding manner than MD simulations, derived from QM Wigner distributions. The combination of Wigner-sampling and GMM-NEA broadening shows promise for wide application in spectroscopic analysis and predictions, offering a computationally efficient alternative to traditional methods.

Shedding light on the metal-phthalocyanine EXAFS spectra through classical and ab initio molecular dynamics.

Extended X-Ray Absorption Fine Structure (EXAFS) theoretical spectra for some 3d transition metal-phthalocyanines-FePc, NiPc, CuPc, and ZnPc-are presented. Their complexity and rigidity make them a good testbed for the development of theoretical strategies that can complement the difficulties present in the experimental spectrum fitting. Classical and ab initio molecular dynamics trajectories are generated and employed as a source of structural information to compute average spectra for each MPc species. The original ZnPc force field employed in the classical molecular dynamics simulations has been modified in order to improve the agreement with the experimental EXAFS spectrum, and the modification strategy-based on MP2 optimized structures-being extended to the rest of MPcs. Both types of trajectories, classical and ab initio, provide very similar results, showing in all cases the main features present in the experimental spectra despite the different simulation timescales employed. Spectroscopical information has been analyzed on the basis of shells and legs contributions, making possible the comparison with the experimental fitting approaches. According to the simulations results, the simple relationships employed in the fitting process to define the dependence of the Debye Waller factors associated with multiple scattering paths with those of single scattering paths are reasonable. However, a lack of multiple backscattering paths contributions is found due to the intrinsic rigidity of the chemical motif (macrocycle). Its consequences in the Debye Waller factors of the fitted contributions are discussed.

A Coupled EXAFS-Molecular Dynamics Study on PuO2+ and NpO2+ Hydration: The Importance of Electron Correlation in Force-Field Building.

The physicochemical properties of the monovalent actinyl cations, PuO2+ and NpO2+, in water have been studied by means of classical molecular dynamic simulations. A specific set of cation-water intermolecular potentials based on ab initio potential energy surfaces has been built on the basis of the hydrated ion concept. The TIP4P water model was adopted. Given the paramagnetic character of these actinyls, the cation-water interaction energies were computed from highly correlated wave functions using the NEVPT2 method. It is shown that the multideterminantal character of the wave function has a relevant effect on the main distances of the hydrated molecular cations. Several structural, dynamical, and energetic properties of the aqueous solutions have been obtained and analyzed. Structural RDF analysis gives An-Oyl distances of 1.82 and 1.84 Å and An-O(water) distances of 2.51 and 2.53 Å for PuO2+ and NpO2+ in water, respectively. Experimental EXAFS spectra from dilute aqueous solutions of PuO2+ and NpO2+ are revisited and analyzed, assuming tetra- and pentahydration of the actinyl cations. Simulated EXAFS spectra have been computed from the snapshots of the MD simulations. Good agreement with the experimental information available is found. The global analysis leads us to conclude that both PuO2+ and NpO2+ cations in water are stable pentahydrated aqua ions.

Hydration of Heavy Alkaline-Earth Cations Studied by Molecular Dynamics Simulations and X-ray Absorption Spectroscopy.

The physicochemical properties of the three heaviest alkaline-earth cations, Sr2+, Ba2+, and Ra2+ in water have been studied by means of classical molecular dynamics (MD) simulations. A specific set of cation-water intermolecular potentials based on ab initio potential energy surfaces has been built on the basis of the hydrated ion concept. The polarizable and flexible model of water MCDHO2 was adopted. The theoretical-experimental comparison of structural, dynamical, energetic, and spectroscopical properties of Sr2+ and Ba2+ aqueous solutions is satisfactory, which supports the methodology developed. This good behavior allows a reasonable reliability for the predicted Ra2+ physicochemical data not experimentally determined yet. Simulated extended X-ray absorption fine-structure (EXAFS) and X-ray absorption near-edge spectroscopy spectra have been computed from the snapshots of the MD simulations and compared with the experimental information available for Sr2+ and Ba2+. For the Ra2+ case, the Ra L3-edge EXAFS spectrum is proposed. Structural and dynamical properties of the aqua ions for the three cations have been obtained and analyzed. Along the [M(H2O)n]m+ series, the M-O distance for the first-hydration shell is 2.57, 2.81, and 2.93 Å for Sr2+, Ba2+, and Ra2+, respectively. The hydration number also increases when one is going down along the group: 8.1, 9.4, and 9.8 for Sr2+, Ba2+, and Ra2+, respectively. Whereas [Sr(H2O)8]2+ is a typical aqua ion with a well-defined structure, the Ba2+ and Ra2+ hydration provides a picture exhibiting an average between the ennea- and the deca-hydration. These results show a similar chemical behavior of Ba2+ and Ra2+ aqueous solutions and support experimental studies on the removal of Ra-226 of aquifers by different techniques, where Ra2+ is replaced by Ba2+. A comparison of the heavy alkaline ions, Rb+ and Cs+, with the heavy alkaline-earth ions is made.

Identificación de un brote de SARSCoV-2 (Covid-19) en un centro gerontológico de la Ciudad de México.

OBJECTIVE: To describe a Covid-19 outbreak in a gerontological center in Mexico City. MATERIAL AND METHODS: Cross-sectional study in older adults. The association of risk factors for dying from Covid-19 was analyzed using a multiple logistic regression model. RESULTS: One hundred and two elders with an average age of 82.5 ± 8.8 years were included. Fifty-five (54%) tested positive and 47 (46%) were negative for the new coronavirus. Using the multiple logistic regression model, people with frailty had an OR of 11.6 of dying from Covid-19 compared to robust people (p-value = 0.024). CONCLUSION: The Covid-19 outbreak was initially caused by a resident of the center and spread by cross infection. In vulnerable populations, early detection, isolation, and follow-up of contacts should be carried out, as well as the identification of risk factors in order to reduce the spread and mortality caused by SARSCoV-2.

Combining EXAFS and Computer Simulations to Refine the Structural Description of Actinyls in Water.

EXAFS spectroscopy is one of the most used techniques to solve the structure of actinoid solutions. In this work a systematic analysis of the EXAFS spectra of four actinyl cations, [UO2]2+, [NpO2]2+, [NpO2]+ and [PuO2]2+ has been carried out by comparing experimental results with theoretical spectra. These were obtained by averaging individual contributions from snapshots taken from classical Molecular Dynamics simulations which employed a recently developed [AnO2]2+/+ -H2O force field based on the hydrated ion model using a quantum-mechanical (B3LYP) potential energy surface. Analysis of the complex EXAFS signal shows that both An-Oyl and An-OW single scattering paths as well as multiple scattering ones involving [AnO2]+/2+ molecular cation and first-shell water molecules are mixed up all together to produce a very complex signal. Simulated EXAFS from the B3LYP force field are in reasonable agreement for some of the cases studied, although the k= 6-8 Å-1 region is hard to be reproduced theoretically. Except uranyl, all studied actinyls are open-shell electron configurations, therefore it has been investigated how simulated EXAFS spectra are affected by minute changes of An-O bond distances produced by the inclusion of static and dynamic electron correlation in the quantum mechanical calculations. A [NpO2]+-H2O force field based on a NEVPT2 potential energy surface has been developed. The small structural changes incorporated by the electron correlation on the actinyl aqua ion geometry, typically smaller than 0.07 Å, leads to improve the simulated spectrum with respect to that obtained from the B3LYP force field. For the other open-shell actinyls, [NpO2]2+ and [PuO2]2+, a simplified strategy has been adopted to improve the simulated EXAFS spectrum. It is computed taking as reference structure the NEVPT2 optimized geometry and including the DW factors of their corresponding MD simulations employing the B3LYP force field. A better agreement between the experimental and the simulated EXAFS spectra is found, confirming the a priori guess that the inclusion of dynamic and static correlation refine the structural description of the open-shell actinyl aqua ions.

Hydration Structure of the Elusive Ac(III) Aqua Ion: Interpretation of X-ray Absorption Spectroscopy (XAS) Spectra on the Basis of Molecular Dynamics (MD) Simulations.

Knowledge of actinoid solution chemistry has been enriched with the recent synthesis and characterization of the elusive Ac(III) aqua ion, the first one of the series, for which extended X-ray absorption fine structure (EXAFS) and X-ray absorption near-edge structure (XANES) spectra has been recorded. Structural analysis combined with Born-Oppenheimer molecular dynamics simulations lead to suggest a 2.63-2.69 Å range for the Ac-O distance, and a coordination number between 9 and 11. A hydration number as high as 11 would imply the appearance of a sharp coordination number contraction at the beginning of the series. In this work, we present a specific Ac(III)-H2O first-principles-based intermolecular potential, which has been developed following the exchangeable Hydrated Ion model. This potential has been used in classical molecular dynamics (MD) simulations of Ac(III) in water. Results show a well-defined Ac(III) ennea-hydrated aqua ion with a mean Ac-O distance of 2.66 ± 0.02 Å, surrounded by a compact second hydration shell formed by ∼20 H2O centered at 4.9 ± 0.1 Å. The results obtained for the first element of the actinoid series confirm the regular contraction of their aqua ions along the series. Simulated EXAFS and XANES spectra have been computed from the structural information provided by the MD simulation. The agreement with the experimental spectra is satisfactory, validating the results from the computer simulation. An observed hump in the experimental XANES spectrum is interpreted and ascribed to the second hydration shell, being an evidence of the consistency of the Ac(III) hydration shells.

A general study of actinyl hydration by molecular dynamics simulations using ab initio force fields.

A set of new ab initio force fields for aqueous [AnO2]2+/+ (An = Np(vi,v), Pu(vi), Am(vi)) has been developed using the Hydrated Ion (HI) model methodology previously used for [UO2]2+. Except for the non-electrostatic contribution of the HI-bulk water interaction, the interaction potentials are individually parameterized. Translational diffusion coefficients, hydration enthalpies, and vibrational normal mode frequencies were calculated from the MD simulations. Physico-chemical properties satisfactorily agree with experiments validating the robustness of the force field strategy. The solvation dynamics and structure for all hexavalent actinoids are extremely similar and resemble our previous analysis of the uranyl cation. This supports the idea of using the uranyl cation as a reference for the study of other minor actinyls. The comparison between the NpO2 2+ and NpO2 + hydration only provides significant differences in first and second shell distances and second-shell mean residence times. We propose a single general view of the [AnO2]2+/+ hydration structure: aqueous actinyls are amphiphilic anisotropic solutes which are equatorially conventional spherically symmetric cations capped at the poles by clathrate-like water structures.

Extracting the Americyl Hydration from an Americium Cationic Mixture in Solution: A Combined X-ray Absorption Spectroscopy and Molecular Dynamics Study.

Am(VI) solution chemistry differs from that of lighter actinoids, as U, Pu, and Np, where the actinyl [AnO2]2+ is the most stable form and plays an important role in nuclear fuel technology. The behavior of americium in solution shows the trend to stabilize lower oxidation states, mainly Am(III). Riddle and co-workers recently reported the EXAFS and first XANES spectra of an americium-containing aqueous solution where the americyl species is detected in a mixture. We have developed Am3+-H2O and [AmO2]2+-H2O intermolecular potentials based on quantum-mechanical calculations to carry out classical MD simulations of these two cations in water. Structural information extracted from the statistical trajectories has been used to simulate EXAFS and XANES spectra of both solutions. For the Am3+ case the theoretical-experimental agreement for both EXAFS and XANES spectra is satisfactory. This is not the case for the [AmO2]2+ aqueous solutions. However, when an aqueous solution mixture of both cationic forms in a 55/45 [AmO2]2+/Am3+ ratio is considered, the theoretical-experimental agreement is recovered. EXAFS and XANES spectra which would correspond to a pure [AmO2]2+ aqueous solution are proposed. In the XANES case, the main features characterizing the simulated spectrum are consistent with those previously found in the experimental XANES spectra of stable [UO2]2+ and [PuO2]2+ in water.

Effect of Basicity on the Hydrolysis of the Bi(III) Aqua Ion in Solution: An Ab Initio Molecular Dynamics Study.

Hydrolysis of the Bi(III) aqua ion under a range of solution conditions has been studied by means of ab initio molecular dynamics simulations. While the Bi(III) aqua ion is stable in pure water, there is an increasing degree of hydrolysis with the number of hydroxide anions in the medium. This is accompanied by a monotonic decrease of the total coordination number to an asymptotic value of ∼6, reached under extreme basicity conditions. Comparison of the simulated Bi(III) hydrolyzed species with the experimental species distribution at different degrees of basicity suggests that, at the PBE/DFT level of theory here employed, liquid water shows an overly acidic character. Predictions of theoretical EXAFS and XANES spectra were generated from the AIMD trajectories for different Bi hydrolyzed species, [Bi(HO)m(H2O)n]3-m+, m = 0-3 and n = 7-2. Comparison with available experimental spectra is presented. Spectral features joined to the degree of hydrolysis and hydration are analyzed.

The hydration structure of the heavy-alkalines Rb+ and Cs+ through molecular dynamics and X-ray absorption spectroscopy: surface clusters and eccentricity.

Physicochemical properties of the two heaviest stable alkaline cations, Rb+ and Cs+, in water have been examined from classical molecular dynamics (MD) simulations. Alkaline cation-water intermolecular potentials have been built from ab initio interaction energies of [M(H2O)n]+ clusters. Unlike in the case of other monatomic metal cations, the sampling needed the inclusion of surface clusters to properly describe the interactions. The first coordination shell is found at an average M-O distance of 2.87 Å and 3.12 Å for Rb+ and Cs+, respectively, with coordination numbers of 8 and 10. Structural, dynamical and energetic properties are discussed on the basis of the delicate compromise among the ion-water and water-water interactions which contribute almost on the same foot to the definition of the solvent structure around the ions. A significant asymmetry is detected in the Rb+ and Cs+ first hydration shell. Reorientational times of first-shell water molecules for Cs+ support a clear structure-breaking nature for this cation, whereas the Rb+ values do not differ from pure water behavior. Experimental EXAFS and XANES spectra have been compared to simulated ones, obtained by means of application of the FEFF code to a set of statistically significant structures taken from the MD simulations. Due to the presence of multi-excitations in the absorption spectra, theoretical-experimental agreement for the EXAFS spectra is reached when the multi-excitations are removed from the experimental spectra.

Sarcocystis masoni, n. sp. (Apicomplexa: Sarcocystidae), and redescription of Sarcocystis aucheniae from llama (Lama glama), guanaco (Lama guanicoe) and alpaca (Vicugna pacos).

There is considerable confusion concerning the species of Sarcocystis in South American camelids (SAC). Several species names have been used; however, proper descriptions are lacking. In the present paper, we redescribe the macroscopic sarcocyst forming Sarcocystis aucheniae and describe and propose a new name, Sarcocystis masoni for the microscopic sarcocyst forming species. Muscles samples were obtained from llamas (Lama glama) and guanacos (Lama guanicoe) from Argentina and from alpacas (Vicugna pacos) and llamas from Peru. Individual sarcocysts were processed by optical and electron microscopy, and molecular studies. Microscopic sarcocysts of S. masoni were up to 800 µm long and 35-95 µm wide, the sarcocyst wall was 2·5-3·5 µm thick, and had conical to cylindrical villar protrusions (vp) with several microtubules. Each vp had 11 or more rows of knob-like projections. Seven 18S rRNA gene sequences obtained from sarcocysts revealed 95-96% identity with other Sarcocystis spp. sequences reported in the GenBank. Sarcocysts of S. aucheniae were macroscopic, up to 1·2 cm long and surrounded by a dense and laminar 50 µm thick secondary cyst wall. The sarcocyst wall was up to 10 µm thick, and had branched vp, appearing like cauliflower. Comparison of the 11 sequences obtained from individual macroscopic cysts evidenced a 98-99% of sequence homology with other S. aucheniae sequences. In conclusion, 2 morphologically and molecularly different Sarcocystis species, S. masoni (microscopic cysts) and S. aucheniae (macroscopic cysts), were identified affecting different SAC from Argentina and Peru.

A hydrated ion model of [UO2]2+ in water: Structure, dynamics, and spectroscopy from classical molecular dynamics.

A new ab initio interaction potential based on the hydrated ion concept has been developed to obtain the structure, energetics, and dynamics of the hydration of uranyl in aqueous solution. It is the first force field that explicitly parameterizes the interaction of the uranyl hydrate with bulk water molecules to accurately define the second-shell behavior. The [UO2(H2O)5]2+ presents a first hydration shell U-O average distance of 2.46 Å and a second hydration shell peak at 4.61 Å corresponding to 22 molecules using a coordination number definition based on a multisite solute cavity. The second shell solvent molecules have longer mean residence times than those corresponding to the divalent monatomic cations. The axial regions are relatively de-populated, lacking direct hydrogen bonding to apical oxygens. Angle-solved radial distribution functions as well as the spatial distribution functions show a strong anisotropy in the ion hydration. The [UO2(H2O)5]2+ solvent structure may be regarded as a combination of a conventional second hydration shell in the equatorial and bridge regions, and a clathrate-like low density region in the axial region. Translational diffusion coefficient, hydration enthalpy, power spectra of the main vibrational modes, and the EXAFS spectrum simulated from molecular dynamics trajectories agree fairly well with the experiment.

Theoretical study on the hydrophobic and hydrophilic hydration on large solutes: The case of phthalocyanines in water.

A theoretical study on the hydration phenomena of three representative Phthalocyanines (Pcs): the metal-free, H2Pc, and the metal-containing, Cu-phthalocyanine, CuPc, and its soluble sulphonated derivative, [CuPc(SO3)4](4-), is presented. Structural and dynamic properties of molecular dynamics trajectories of these Pcs in solution were evaluated. The hydration shells of the Pcs were defined by means of spheroids adapted to the solute shape. Structural analysis of the axial region compared to the peripheral region indicates that there are no significant changes among the different macrocycles, but that of [CuPc(SO3)4](4-), where the polyoxoanion presence induces a typically hydrophilic hydration structure. The analyzed water dynamic properties cover mean residence times, translational and orientational diffusion coefficients, and hydrogen bond network. These properties allow a thorough discussion about the simultaneous existence of hydrophobic and hydrophilic hydration in these macrocycles, and indicate the trend of water structure to well define shells in the environment of hydrophobic solutes. The comparison between the structural and dynamical analysis of the hydration of the amphipathic [CuPc(SO3)4](4-) and the non-soluble Cu-Pc shows a very weak coupling among the hydrophilic and hydrophobic fragments of the macrocycle. Quantitative results are employed to revisit the iceberg model proposed by Frank and Evans, leading to conclude that structure and dynamics support a non-strict interpretation of the iceberg view, although the qualitative trends pointed out by the model are supported.

Effect of the meso-substituent in the Hückel-to-Möbius topological switches.

Expanded porphyrins have emerged as a new promising class of molecules for the creation of new Hückel-to-Möbius topological switches with distinct aromaticities and magnetic and electric properties. In this work, we report a theoretical investigation of the conformational switch between the Hückel planar and the singly twisted Möbius structure for eight different meso-substituted [28]-hexaphyrins (with different steric effects and electron-withdrawing and -releasing character). Our results show how a change in the nature of the meso-substituent is able to turn an endothermic interconversion process with a high energy barrier into an exothermic and almost barrierless Hückel-Möbius transition. We also provide a thorough analysis of the main factors (aromaticity, intramolecular hydrogen bonds, ring strain, and steric effects) that play a role in this interconversion process. Overall, these results are very relevant to find new ways to control the thermochemistry and kinetics of these topological switches and even "freeze" the switch in the desired Möbius or Hückel conformation.

Collecting high-order interactions in an effective pairwise intermolecular potential using the hydrated ion concept: the hydration of Cf³âº.

This work proposes a new methodology to build interaction potentials between a highly charged metal cation and water molecules. These potentials, which can be used in classical computer simulations, have been fitted to reproduce quantum mechanical interaction energies (MP2 and BP86) for a wide range of [M(H2O)n](m+)(H2O)ℓ clusters (n going from 6 to 10 and ℓ from 0 to 18). A flexible and polarizable water shell model (Mobile Charge Density of Harmonic Oscillator) has been coupled to the cation-water potential. The simultaneous consideration of poly-hydrated clusters and the polarizability of the interacting particles allows the inclusion of the most important many-body effects in the new polarizable potential. Applications have been centered on the californium, Cf(III) the heaviest actinoid experimentally studied in solution. Two different strategies to select a set of about 2000 structures which are used for the potential building were checked. Monte Carlo simulations of Cf(III)+500 H2O for three of the intermolecular potentials predict an aquaion structure with coordination number close to 8 and average R(Cf-O) in the range 2.43-2.48 Å, whereas the fourth one is closer to 9 with R(Cf-O) = 2.54 Å. Simulated EXAFS spectra derived from the structural Monte Carlo distribution compares fairly well with the available experimental spectrum for the simulations bearing 8 water molecules. An angular distribution similar to that of a square antiprism is found for the octa-coordination.

The structural landscape of the immunoglobulin fold by large-scale de novo design.

De novo designing immunoglobulin-like frameworks that allow for functional loop diversification shows great potential for crafting antibody-like scaffolds with fully customizable structures and functions. In this work, we combined de novo parametric design with deep-learning methods for protein structure prediction and design to explore the structural landscape of 7-stranded immunoglobulin domains. After screening folding of nearly 4 million designs, we have assembled a structurally diverse library of ~50,000 immunoglobulin domains with high-confidence AlphaFold2 predictions and structures diverging from naturally occurring ones. The designed dataset enabled us to identify structural requirements for the correct folding of immunoglobulin domains, shed light on ß-sheet-ß-sheet rotational preferences and how these are linked to functional properties. Our approach eliminates the need for preset loop conformations and opens the route to large-scale de novo design of immunoglobulin-like frameworks.