Felipe Rodrigues Souza

Alzheimer's disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu²⁺ and Zn²⁺, directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1-16 and 25-35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu²⁺ ions slightly decreases the energy associated with the aggregation of the β-amyloid 1-16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn²⁺ ions do not reduce the energy barrier for the aggregation of the β-amyloid 1-16 fragment in aqueous solution. Zn²⁺ displays a higher affinity for the acidic residues of Aβ_1-16, establishing more frequent, yet less selective, contacts compared to those observed for Cu²⁺ ions. The main finding is that Cu²⁺ and Zn²⁺ ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu²⁺ favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn²⁺ does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu²⁺, identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer's disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer's disease.

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

This viewpoint intends to show recent open issues of using coarse grained models in molecular dynamics simulation. It reviews the current knowledge of the comparison between experimental and simulation data of structural and physical chemical properties that depend on the hydrophilic and hydrophobic behavior of the molecule.

The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood–brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

The lipophilicity of cholesterol was successfully investigated by using coarse-grained molecular dynamics and umbrella sampling. The previous coarse grained cholesterol models in literature are more hydrophobic than our model. The Gibbs free energy of transferring cholesterol from octanol to water phase (Go/w) and the octanol/water partitioning coefficient (logP) were calculated to be 11.880.08 kcal mol-1 and 8.720.06, respectively. The latter is in excellent agreement with bioinformatics tools, which are standard methods to predict the lipophilicity giving excellent octanol/water partitioning coefficients compared with experimental ones for different molecules. To the best of our knowledge, we also performed the first experimental direct measurement of this important property for cholesterol. The experimental octanol/water partitioning coefficient of cholesterol was measured to be 8.86±0.79, which is in excellent agreement with our calculated logP from a parameterized coarse grained cholesterol model. This shows the significance of systematic optimization of the lipophilicity for coarse-graining biologically important molecules with complicated molecular structures and hydrophobic character like cholesterol.