Polarizable MD and QM/MM Investigation of Acrylamide-based Leads to Target the Main Protease of SARS-CoV-2

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for the replication of the virus causing the COVID-19 pandemic. Because there is no known homologue in humans, it has been proposed as a primary target for antiviral drug development. Here, we explore the potential of five acrylamide warhead molecules as possible leads to target MPro by polarizable MD and QM/MM calculations. All calculations involving a classical potential were calculated with the AMOEBA polarizable force field, while electronic structure calculations were performed within the framework of density functional theory. Our MD simulations show that at least one of the analyzed compounds may show promise as a lead for further development as a non-covalent inhibitor. The QM/MM calculations suggest that the compound could be considered as a non-covalent inhibitor, since the formation of a covalent bond with Cys145 has an unfavorable kinetic barrier for that compound

Relative Cooperativity in Neutral and Charged Molecular Clusters Using QM/MM Calculations

QM/MM methods have been used to study electronic structure properties and chemical reactivity in complex molecular systems where direct electronic structure calculations are not feasible. In our previous work, we showed that non-polarizable force fields, by design, describe intermolecular interactions through pairwise interactions, overlooking many-body interactions involving three or more particles. In contrast, polarizable force fields account partially for many-body effects through polarization, but still handle van der Waals and permanent electrostatic interactions pairwise. We showed that despite those limitations, polarizable and non-polarizable force fields, can reproduce relative cooperativity achieved using Density Functional Theory, due to error compensation mechanisms. In this contribution, we assess the performance of QM/MM methods in reproducing these phenomena. Our study highlights the significance of QM region size and force field choice in QM/MM simulations, emphasizing the importance of parameter validation to obtain accurate interaction energy predictions

Structural and Electronic Analysis of the Octarepeat Region of Prion Protein with Four Cu(II) by Polarizable MD and QM/MM Simulations

The prion protein, located mainly in neurons, is believed to play the role of metal ion transporter. A 32-residue region of the N-terminal domain, known as octarepeat, can bind up to four Cu ions. Different coordination modes have been observed and are strongly dependent on Cu concentration. Many theoretical studies carried out so far have focused on studying the coordination modes of a single copper ion. In this work we investigate the octarepeat region coordinated with four copper ions. Molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations using the polarizable AMOEBA force field have been carried out. Results indicate that the 4Cu-octarepeat complex forms a globular structure, in agreement with experimental results. Subsequent QM/MM simulations on several snapshots suggests the system is in a high-spin quintet state, with all Cu ions bearing one single electron, and all unpaired electrons are ferromagnetically coupled

Seamless integration of GEM, a density based-force field, for QM/MM simulations via LICHEM, Psi4 and Tinker-HP

Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have become an essential tool in computational chemistry, particularly for analyzing complex biological and condensed phase systems. Building on this foundation, our work presents a novel implementation of the Gaussian Electrostatic Model (GEM), a polarizable density-based force field, within the QM/MM framework. This advancement provides seamless integration, enabling efficient and optimized QM/GEM calculations in a single step using the LICHEM Code. We have successfully applied our implementation to water dimers and hexamers, demonstrating the ability to handle water systems with varying numbers of water molecules. Moreover, we have extended the application to describe the double proton transfer of the aspartic acid dimer in a box of water, which highlights the method\u27s proficiency in investigating heterogeneous systems. Our implementation offers the flexibility to perform on-the-fly density fitting or to utilize pre-fitted coefficients to estimate exchange and Coulomb contributions. This flexibility enhances efficiency and accuracy in modeling molecular interactions, especially in systems where polarization effects are significant

Cooperativity and Frustration Effects (or Lack Thereof) in Polarizable and Non-Polarizable Force Fields

Understanding cooperativity and frustration is crucial for studying biological processes, such as molecular recognition and protein aggregation. Force fields have been extensively utilized to explore cooperativity in the formation of protein secondary structures and self-assembled systems. Multiple studies have demonstrated that polarizable force fields provide more accurate descriptions of this phenomenon compared to fixed-charge pairwise non-polarizable force fields, thanks to the incorporation of polarization effects. In this study, we assess the performance of the AMOEBA polarizable force field and the AMBER and OPLS non-polarizable pairwise force fields in capturing positive and negative cooperativity recently explored in neutral and charged molecular clusters using Density Functional Theory. Our findings show that polarizable and non-polarizable force fields qualitatively reproduce the relative cooperativity observed in electron structure calculations. However, AMBER and OPLS fail in describing absolute cooperativity. In contrast, AMOEBA accounts for absolute cooperativity by considering interactions beyond pairwise interactions. According to the energy decomposition analysis, it is observed that the electrostatic interactions calculated with the AMBER and OPLS force fields seems to play an important and counter-intuitive role in reproducing the adiabatic interaction energies calculated with Density Functional Theory. However, it is important to note that these force fields, due to their nature, do not explicitely incorporate many-body effects, which limits their ability to accurately describe cooperativity. On the other hand, frustration in polarizable and non-polarizable force fields is caused by changes in bond stretching and angle bending terms of the building blocks when they are forming a complex

Impact of an Ionic Liquid Solution on Horseradish Peroxidase Activity

Horseradish peroxidase (HRP) is an enzyme that oxidizes pollutants from wastewater. A previous report indicated that peroxidases can have an enhancement in initial enzymatic activity in an aqueous solution of 0.26 M 1-ethyl-3-methylimidazolium ethyl sulfate ([EMIm][EtSO4]) at neutral pH. However, the atomistic details remain elusive. In the enzymatic landscape of HRP, compound II (Cpd II) plays a key role and involves a histidine (H42) residue. Cpd II exists as oxoferryl (2a) or hydroxoferryl (2b(FeIV)) forms, where 2a is the predominantly observed form in experimental studies. Intriguingly, the ferric 2b(FeIII) form seen in synthetic complexes has not been observed in HRP. Here, we have investigated the structure and dynamics of HRP in pure water and aqueous [EMIm][EtSO4] (0.26 M), as well as the reaction mechanism of 2a to 2b conversion using polarizable molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations. When HRP is solvated in aq [EMIm][EtSO4], the catalytic water displaces, and H42 directly orients over the ferryl moiety, allowing a direct proton transfer (PT) with a significant energy barrier reduction. Conversely, in neat water, the reaction of 2a to 2b follows the previously reported mechanism. We further investigated the deprotonated form of H42. Analysis of the electric fields at the active site indicates that the aq [EMIm][EtSO4] medium facilitates the reaction by providing a more favorable environment compared with the system solvated in neat water. Overall, the atomic level supports the previous experimental observations and underscores the importance of favorable electric fields in the active site to promote catalysis

Impact of an Ionic Liquid Solution on Horseradish Peroxidase Activity

Horseradish peroxidase (HRP) is an enzyme that oxidizes pollutants from wastewater. A previous report indicated that peroxidases can have an enhancement in initial enzymatic activity in an aqueous solution of 0.26 M 1-ethyl-3-methylimidazolium ethyl sulfate ([EMIm][EtSO4]) at neutral pH. However, the atomistic details remain elusive. In the enzymatic landscape of HRP, compound II (Cpd II) plays a key role and involves a histidine (H42) residue. Cpd II exists as oxoferryl (2a) or hydroxoferryl (2b(FeIV)) forms, where 2a is the predominantly observed form in experimental studies. Intriguingly, the ferric 2b(FeIII) form seen in synthetic complexes has not been observed in HRP. Here, we have investigated the structure and dynamics of HRP in pure water and aqueous [EMIm][EtSO4] (0.26 M), as well as the reaction mechanism of 2a to 2b conversion using polarizable molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations. When HRP is solvated in aq [EMIm][EtSO4], the catalytic water displaces, and H42 directly orients over the ferryl moiety, allowing a direct proton transfer (PT) with a significant energy barrier reduction. Conversely, in neat water, the reaction of 2a to 2b follows the previously reported mechanism. We further investigated the deprotonated form of H42. Analysis of the electric fields at the active site indicates that the aq [EMIm][EtSO4] medium facilitates the reaction by providing a more favorable environment compared with the system solvated in neat water. Overall, the atomic level supports the previous experimental observations and underscores the importance of favorable electric fields in the active site to promote catalysis