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Computational modeling (CM) is a versatile scientific methodology used to examine the properties and behavior of complex systems, such as polymeric materials for biomedical bioengineering. CM has emerged as a primary tool for predicting, setting up, and interpreting experimental results. Integrating in silico and in vitro experiments accelerates scientific advancements, yielding quicker results at a reduced cost. While CM is a mature discipline, its use in biomedical engineering for biopolymer materials has only recently gained prominence. In biopolymer biomedical engineering, CM focuses on three key research areas: (A) Computer-aided design (CAD/CAM) utilizes specialized software to design and model biopolymers for various biomedical applications. This technology allows researchers to create precise three-dimensional models of biopolymers, taking into account their chemical, structural, and functional properties. These models can be used to enhance the structure of biopolymers and improve their effectiveness in specific medical applications. (B) Finite element analysis, a computational technique used to analyze and solve problems in engineering and physics. This approach divides the physical domain into small finite elements with simple geometric shapes. This computational technique enables the study and understanding of the mechanical and structural behavior of biopolymers in biomedical environments. (C) Molecular dynamics (MD) simulations involve using advanced computational techniques to study the behavior of biopolymers at the molecular and atomic levels. These simulations are fundamental for better understanding biological processes at the molecular level. Studying the wide-ranging uses of MD simulations in biopolymers involves examining the structural, functional, and evolutionary aspects of biomolecular systems over time. MD simulations solve Newton's equations of motion for all-atom systems, producing spatial trajectories for each atom. This provides valuable insights into properties such as water absorption on biopolymer surfaces and interactions with solid surfaces, which are crucial for assessing biomaterials. This review provides a comprehensive overview of the various applications of MD simulations in biopolymers. Additionally, it highlights the flexibility, robustness, and synergistic relationship between in silico and experimental techniques.

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Glutathione transferases (GSTs EC 2.5.1.18) are critical components of phase II metabolism, instrumental in xenobiotics' metabolism. Their primary function involves conjugating glutathione to both endogenous and exogenous toxic compounds, which increases their solubility and enables their ejection from cells. They also play a role in the transport of non-substrate compounds and immunomodulation, aiding in parasite establishment within its host. The cytosolic GST subfamily is the most abundant and diverse in helminths, and sigma-class GST (GSTσ) belongs to it. This review focuses on three key functions of GSTσ: serving as a detoxifying agent that provides drug resistance, functioning as an immune system modulator through its involvement in prostaglandins synthesis, and acting as a vaccine antigen.

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Taenia solium can cause human taeniasis and/or cysticercosis. The latter can in some instances cause human neurocysticercosis which is considered a priority in disease-control strategies and the prevention of mental health problems. Glutathione transferases are crucial for the establishment and long-term survival of T. solium; therefore, we structurally analyzed the 24-kDa glutathione transferase gene (Ts24gst) of T. solium and biochemically characterized its product. The gene promoter showed potential binding sites for transcription factors and xenobiotic regulatory elements. The gene consists of a transcription start site, four exons split by three introns, and a polyadenylation site. The gene architecture is conserved in cestodes. Recombinant Ts24GST (rTs24GST) was active and dimeric. Anti-rTs24GST serum showed slight cross-reactivity with human sigma-class GST. A 3D model of Ts24GST enabled identification of putative residues involved in interactions of the G-site with GSH and of the H-site with CDNB and prostaglandin D2. Furthermore, rTs24GST showed optimal activity at 45 °C and pH 9, as well as high structural stability in a wide range of temperatures and pHs. These results contribute to the better understanding of this parasite and the efforts directed to fight taeniasis/cysticercosis.

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The extensive spread of COVID-19 in every continent shows that SARS-CoV-2 virus has a higher transmission rate than SARS-CoV virus which emerged in 2002. This results in a global pandemic that is difficult to control. In this investigation, we analyze the interaction of N3 inhibitor and the main protease of SARS-CoV and SARS-CoV-2 by quantum chemistry calculations. Non-covalent interactions involved in these systems were studied using a model of 469 atoms. Density Functional Theory and Quantum Theory of Atoms in Molecules calculations lead us to the conclusion that non-conventional hydrogen bonds are important to describe attractive interactions in these complexes. The energy of these non-conventional hydrogen bonds represents more than a half of the estimated interaction energy for non-covalent contacts. This means that hydrogen bonds are crucial to correctly describe the bonds between inhibitors and the main proteases. These results could be useful for the design of new drugs, since non-covalent interactions are related to possible mechanisms of action of molecules used against these viruses.

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Psychosis is one of the psychiatric disorders that is controlled by dopaminergic drugs such as antipsychotics that have affinity for the dopamine D2 receptor (DRD2). In this investigation we perform quantum chemical calculations of two molecules [dopamine and risperidone] within a large cavity of DRD2 that represents the binding site of the receptor. Dopamine is an endogenous neurotransmitter and risperidone is a second-generation antipsychotic. Non-covalent interactions of dopamine and risperidone with DRD2 are analyzed using the Quantum Theory of Atoms in Molecules (QTAIM) and the Non-Covalent Interaction index (NCI). The QTAIM results show that these molecules strongly interact with the receptor. There are 22 non-covalent interactions for dopamine and 54 for risperidone. The electron density evaluated at each critical binding point is small in both systems but it is higher for dopamine than for risperidone, indicating that the interactions of DRD2 with the first are stronger than with the second molecule. However, the binding energy is higher for risperidone (-72.6 kcal mol-1) than for dopamine (-22.8 kcal mol-1). Thus, the strength of the binding energy is due to the number of contacts rather than the strength of the interactions themselves. This could be related to the ability of risperidone to block DRD2 and may explain the efficacy of this drug for controlling the symptoms of schizophrenia, but likewise its secondary effects.

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The original publication of this article contained a number of grammatical errors. Unfortunately, an incorrect version of the file that did not include some final language editing was inadvertently published online. The original article has been corrected.

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Human cystatin C (HCC) binds and inhibits all types of cysteine proteases from the papain family, including cathepsins (a group of enzymes that participate in a variety of physiological processes), which are some of its natural targets. The affinities of diverse proteases for HCC, expressed as equilibrium binding constants (Kb), range from 106 to 1014 M-1. Isothermal titration calorimetry (ITC) is one of the most useful techniques to characterize the thermodynamics of molecular associations, making it possible to dissect the binding free energy into its enthalpic and entropic components. This information, together with the structural changes that occur during the different associations, could enable better understanding of the molecular basis of affinity. Notwithstanding the high sensitivity of modern calorimeters, ITC requires protein concentrations in at least the 10-100 µM range to obtain reliable data, and it is known that HCC forms oligomers in this concentration range. We present herein a comparative study of the structural, thermal stability, and oligomerization properties of HCC and its stabilized variant (sHCC) L47C/G69C (which possesses an additional disulfide bridge) as well as their binding thermodynamics to the protease chymopapain, analyzed by ITC. The results show that, because sHCC remains monomeric, it is a better reporter than wild-type HCC to characterize the thermodynamics of binding to cysteine proteases.

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The potential energy surface of [Cu(H2O)n]2+ clusters with n = 12, 16, and 18 was explored by using a modified version of the simulated annealing method. Such exploration was carried out by using the PM7 semiempirical method to obtain around 100,000 isomers, which provide candidates to be optimized with PBE0-D3, M06-2X, and BHLYP exchange-correlation functionals coupled with the 6-311++G** basis set. These methods based on the Kohn-Sham approach delivered isomers with coordination numbers of 4, 5, and 6. The analysis used to obtain coordination numbers was based on geometrical parameters and the quantum theory of atoms in molecules (QTAIM) approach. Our methodology found only one isomer with fourfold coordination and its probabilities to appear in these clusters are quite small for high temperatures. The procedure used in this article predicts important populations of fivefold and sixfold coordination clusters, in fact, the fivefold coordination dominates for PBE0-D3 and BHLYP methods, although the sixfold coordination starts to be important when the number of water molecules is increased. The nature of axial and equatorial contacts is discussed in the context of the QTAIM and the noncovalent interaction index (NCI), which gives a clear classification of such orientations. Also, these methods suggest a partial covalent interaction between the Cu2+ and water molecules in both positions; equatorial and axial.

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BACKGROUND: Saccharomyces cerevisiae triosephosphate isomerase (yTIM) is a dimeric protein that shows noncoincident unfolding and refolding transitions (hysteresis) in temperature scans, a phenomenon indicative of the slow forward and backward reactions of the native-unfolded process. Thermal unfolding scans suggest that no stable intermediates appear in the unfolding of yTIM. However, reported evidence points to the presence of residual structure in the denatured monomer at high temperature. RESULTS: Thermally denatured yTIM showed a clear trend towards the formation of aggregation-prone, ß-strand-like residual structure when pH decreased from 8.0 to 6.0, even though thermal unfolding profiles retained a simple monophasic appearance regardless of pH. However, kinetic studies performed over a relatively wide temperature range revealed a complex unfolding mechanism comprising up to three observable phases, with largely different time constants, each accompanied by changes in secondary structure. Besides, a simple sequential mechanism is unlikely to explain the observed variation of amplitudes and rate constants with temperature. This kinetic complexity is, however, not linked to the appearance of residual structure. Furthermore, the rate constant for the main unfolding phase shows small, rather unvarying values in the pH region where denatured yTIM gradually acquires a ß-strand-like conformation. It appears, therefore, that the residual structure has no influence on the kinetic stability of the native protein. However, the presence of residual structure is clearly associated with increased irreversibility. CONCLUSIONS: The slow temperature-induced unfolding of yeast TIM shows three kinetic phases. Rather than a simple sequential pathway, a complex mechanism involving off-pathway intermediates or even parallel pathways may be operating. ß-strand-type residual structure, which appears below pH 8.0, is likely to be associated with increased irreversible aggregation of the unfolded protein. However, this denatured form apparently accelerates the refolding process.

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Previously, we applied in vitro evolution to generate the thermoresistant triple mutant H62R/N223Y/M319I of ß-glucosidase B (BglB) from Paenibacillus polymyxa. In order to dissect the energetic contributions to protein stabilization achieved by these mutations, we measured the kinetic constants of the heat denaturation of wild type BglB, the triple mutant and the three single mutants (H62R, N223Y, M319I) by circular dichroism at various temperatures. Our results show that all four mutants delayed the denaturation process. Based on the Transition State theory, the increase of the activation barrier for the thermal denaturation of the triple mutant (ΔΔG ( N→TS )) is equivalent to that produced by the sum of the contributions from the three single mutants, whose C ( ß ) s are located at least 18 Å apart. This analysis provides a formal demonstration of the generally accepted idea that protein thermal stability can be increased through sequential addition of individual mutations. Each of the mutations described here contribute in part to the overall effect, which in this case affects the unfolding barrier.

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