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Item Rational Design of Hydrogels for Cationic Antimicrobial Peptide Delivery: A Molecular Modeling ApproachAutores: Pereira, Alfredo; Valdés-Muñoz, Elizabeth; Marican, Adolfo; Cabrera-Barjas, Gustavo; Vijayakumar, Sekar; Valdés, Óscar; Rafael, Diana; Andrade, Fernanda; Abaca, Paulina; Bustos, Daniel; Durán-Lara, Esteban F.In light of the growing bacterial resistance to antibiotics and in the absence of the development of new antimicrobial agents, numerous antimicrobial delivery systems over the past decades have been developed with the aim to provide new alternatives to the antimicrobial treatment of infections. However, there are few studies that focus on the development of a rational design that is accurate based on a set of theoretical-computational methods that permit the prediction and the understanding of hydrogels regarding their interaction with cationic antimicrobial peptides (cAMPs) as potential sustained and localized delivery nanoplatforms of cAMP. To this aim, we employed docking and Molecular Dynamics simulations (MDs) that allowed us to propose a rational selection of hydrogel candidates based on the propensity to form intermolecular interactions with two types of cAMPs (MP-L and NCP-3a). For the design of the hydrogels, specific building blocks were considered, named monomers (MN), co-monomers (CM), and cross-linkers (CL). These building blocks were ranked by considering the interaction with two peptides (MP-L and NCP-3a) as receptors. The better proposed hydrogel candidates were composed of MN3-CM7-CL1 and MN4-CM5-CL1 termed HG1 and HG2, respectively. The results obtained by MDs show that the biggest differences between the hydrogels are in the CM, where HG2 has two carboxylic acids that allow the forming of greater amounts of hydrogen bonds (HBs) and salt bridges (SBs) with both cAMPs. Therefore, using theoretical-computational methods allowed for the obtaining of the best virtual hydrogel candidates according to affinity with the specific cAMP. In conclusion, this study showed that HG2 is the better candidate for future in vitro or in vivo experiments due to its possible capacity as a depot system and its potential sustained and localized delivery system of cAMP.Item Testing Affordable Strategies for the Computational Study of Reactivity in Cysteine Proteases: The Case of SARS-CoV-2 3CL Protease InhibitionAutores: Ramos Guzmán, Carlos A.; Velázquez Libera, José Luis; Ruíz Pernía, Javier J.; Tuñón, IñakiCysteine proteases are an important target for the development of inhibitors that could be used as drugs to regulate the activity of these kinds of enzymes involved in many diseases, including COVID-19. For this reason, it is important to have methodological tools that allow a detailed study of their activity and inhibition, combining computational efficiency and accuracy. We here explore the performance of different quantum mechanics/molecular mechanics methods to explore the inhibition reaction mechanism of the SARS-CoV-2 3CL protease with a hydroxymethyl ketone derivative. We selected two density functional theory (DFT) functionals (B3LYP and M06-2X), two semiempirical Hamiltonians (AM1d and PM6), and two tight-binding DFT methods (DFTB3 and GFN2-xTB) to explore the free energy landscape associated with this reaction. We show that it is possible to obtain an accurate description combining molecular dynamics simulations performed using tight-binding DFT methods and single-point energy corrections at a higher QM description. The use of a computational strategy that provides reliable results at a reasonable computational cost could assist the in silico screening of possible candidates during the design of new drugs directed against cysteine proteases.Item Molecular Dynamics Study on the Influence of the CLK Motif on the Structural Stability of Collagen-Like Peptides Adsorbed on Gold NanosurfacesAutores: Galaz Araya, Constanza Bernardita; Galaz Davison, Pablo; Cortes Arriagada, Diego; Zamora Brito, Ricardo Andrés; Poblete Vilches, Horacio Nelson GermánThe role of the cysteine-leucine-lysine (CLK) motif in enhancing the structural stability of collagen-like peptides (CLPs) adsorbed onto gold nanosurfaces is investigated in this study. The effects of CLK inclusion in CLPs on peptide adsorption, structural stability, and hydrogen bonding behavior in both solvent and surface environments are analyzed by using molecular dynamics simulations. It is shown that CLPs containing the CLK motif (P1-CLK) exhibit stronger binding, greater water displacement, and more stable conformations compared to non-modified CLPs (P1). Additionally, energetically favorable behavior is observed in simulations with multiple peptides, leading to enhanced surface coverage for P1-CLK. These findings indicate that the CLK motif is crucial for optimizing peptide-surface interactions with potential applications in biomaterials design.Item Dummy Template Molecularly Imprinted Polymers for Electrochemical Detection of Cardiac Troponin I: A Combined Computational and Experimental ApproachAutores: Sadeghi Googheri, Mohammad Sadegh; Campagnol, Davide; Ugo, Paolo; Hozhabr Araghi, Samira; Karimian, NajmehCardiac troponin I (cTnI) is a crucial biomarker for the early detection of acute myocardial infarction (AMI), playing a significant role in cardiac health assessment. Molecularly imprinted polymers (MIPs) are valued for their stability, ease of fabrication, reusability, and selectivity. However, using the analyte as a template can be costly, especially if the analyte is expensive. In such cases, a dummy template (DT) with similar chemico-physical properties can be useful. This study aimed to design a DT-MIP for cTnI detection using cytochrome c (Cyt c) as the template, combining computational and experimental approaches. Molecular docking identified binding sites on Cyt c and cTnI for poly(o-phenylenediamine) (5PoPD) pentamers. Interactions and binding energies were examined using all-atom molecular dynamics (MDs) simulations and structural interaction fingerprint (SIFt) calculations. A DT-MIP-modified electrode for cTnI detection was prepared by electropolymerizing o-PD in the presence of Cyt c as a dummy template. Electrochemical techniques monitored the electropolymerization, template removal, and binding of the target analyte. The experimental results showed that the DT-MIPs exhibited a high binding affinity for cTnI, consistent with the binding energies observed in MD simulations. The satisfactory correlation between experimental and computational results validated our model-based approach for the rational design of dummy template molecularly imprinted polymers.
