Search

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to Mpro. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization., Noncovalent inhibitors with low-nanomolar potency are reported for the main protease of SARS-CoV-2. X-ray crystal structures of complexes are provided, and antiviral activity is also demonstrated using infected cells.

Infrared spectroscopy can provide significant insight into the structures and dynamics of molecules of all sizes. The information that is contained in the spectrum is, however, often not easily extracted without the aid of theoretical calculations or simulations. We present here the calculation of the infrared spectra of a database of 703 gas phase compounds with four different force fields (CGenFF, GAFF-BCC, GAFF-ESP, and OPLS) using normal-mode analysis. Modern force fields increasingly use virtual sites to describe, e.g., lone-pair electrons or the o -holes on halogen atoms. This requires some adaptation of code to perform normal-mode analysis of such compounds, the implementation of which into the GROMACS software is briefly described as well. For the quantitative comparison of the obtained spectra with experimental reference data, we discuss the application of two different statistical correlation coefficients, Pearson and Spearman. The advantages and drawbacks of the different methods of comparison are discussed, and we find that both methods of comparison give the same overall picture, showing that present force field methods cannot match the performance of quantum chemical methods for the calculation of infrared spectra.

Size-dependent solubility is prevalent in atmospheric nanoparticles, but a molecular level understanding is still insufficient, especially for organic compounds. Here, we performed molecular dynamics simulations to investigate the size dependence of succinic acid solvation on the scale of ~1-4 nm with the potential of mean forces method. Our analyses reveal that the surface preference of succinic acid is stronger for a droplet than the slab of the same size, and the surface propensity is enhanced due to the curvature effect as the droplet becomes smaller. Energetic analyses show that such surface preference is primarily an enthalpic effect in both systems, while the entropic effect further enhances the surface propensity in droplets. On the other hand, with decreasing droplet size, the solubility of succinic acid in the internal bulk volume may decrease, imposing an opposite effect on the size dependence of solubility as compared with the enhanced surface propensity. Meanwhile, structural analyses, however, show that the surface to internal bulk volume ratio increases drastically, especially when considering the surface in respect to succinic acid, e.g., for droplet with radius of 1 nm, the internal bulk volume would be already close to zero for the succinic acid molecule.

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with Mpro, 17 were chosen for evaluation in a kinetic assay for Mpro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1’, and P2 pockets of Mpro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.

Spectroscopic analysis of compounds is typically combined with density functional theory, for instance, for assigning vibrational frequencies, limiting application to relatively small compounds. Accurate classical force fields could, in principle, complement these quantum-chemical tools. A relatively simple way to validate vibrational frequencies is by computing thermochemical properties. We present such a validation for over 1800 small molecules using the harmonic approximation. Two popular empirical force fields (GAFF and CGenFF) are compared to experimental data and results from Gaussian-4 quantum-chemical calculations. Frequency scaling factors of 1.035 (CGenFF) and 1.018 (GAFF) are derived from the zero-point energies. The force field calculations have larger deviation from experiment than the G4 method for standard entropy, but for heat capacity the results are comparable. For internal thermal energy and zero-point energy the deviations from G4 are relatively small. The work suggests that with some tuning force fields could indeed complement DFT in spectroscopical applications.

Gas-phase electric properties of molecules can be computed routinely using wave function methods or density functional theory (DFT). However, these methods remain computationally expensive for high-throughput screening of the vast chemical space of virtual compounds. Therefore, empirical force fields are a more practical choice in many cases, particularly since force field methods allow one to routinely predict the physicochemical properties in the condensed phases. This work presents Drude polarizable models, to increase the physical realism in empirical force fields, where the core particle is treated as a point charge and the Drude particle is treated either as a 1 s-Gaussian or a ns-Slater ( n = 1, 2, 3) charge density. Systematic parametrization to large high-quality quantum chemistry data obtained from the open access Alexandria Library ( https://doi.org/10.5281/zenodo.1004711 ) ensures the transferability of these parameters. The dipole moments and isotropic polarizabilities of the isolated molecules predicted by the proposed Drude models are in agreement with experiment with accuracy similar to DFT calculations at the B3LYP/aug-cc-pVTZ level of theory. The results show that the inclusion of explicit polarization into the models reduces the root-mean-square deviation with respect to DFT calculations of the predicted dipole moments of 152 dimers and clusters by more than 50%. Finally, we show that the accuracy of the electrostatic interaction energy of the water dimers can be improved systematically by the introduction of polarizable smeared charges as a model for charge penetration.

The harmonic angle bending potential is used in many force fields for (bio)molecular simulation. The force associated with this potential is discontinuous at angles close to 180 degrees, which can lead to numeric instabilities. Angle bending of linear groups, such as alkynes or nitriles, or linear molecules, such as carbon dioxide, can be treated by a simple harmonic potential if we describe the fluctuations as a deviation from a reference position of the central atom, the position of which is determined by the flanking atoms. The force constant for the linear angle potential can be derived analytically from the corresponding force constant in the traditional potential. The new potential is tested on the properties of alkynes, nitriles, and carbon dioxide. We find that the angles of the linear groups remain about 2 degrees closer to 180 degrees using the new potential. The bond and angle force constants for carbon dioxide were tuned to reproduce the experimentally determined frequencies. An interesting finding was that simulations of liquid carbon dioxide under pressure with the new flexible model were stable only when explicitly modeling the long-range Lennard-Jones (LJ) interactions due to the very long-range nature of the LJ interactions (>1.7 nm). In the other tested liquids, we find that a Lennard-Jones cutoff of 1.1 nm yields similar results as the particle mesh Ewald algorithm for LJ interactions. Algorithmic factors influencing the stability of liquid simulations are discussed as well. Finally, we demonstrate that the linear angle potential can be used in free energy perturbation calculations. (c) 2020 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

A longstanding goal of computational chemistry is to predict the state of materials in all phases with a single model. This is particularly relevant for materials that are difficult or dangerous to handle or compounds that have not yet been created. Progress towards this goal has been limited as most work has concentrated on just one phase, often determined by particular applications. In the framework of the development of the Alexandria force field we present here new polarizable force fields for alkali halides with Gaussian charge distributions for molecular dynamics simulations. We explore different descriptions of the Van der Waals interaction, like the commonly applied 12-6 Lennard-Jones (LJ), and compare it to \softer" ones, such as 8-6 LJ, Buckingham and a modified Buckingham potential. Our results for physico-chemical properties of the gas, liquid and solid phase of alkali halides, are compared to experimental data and calculations with reference polarizable and non-polarizable force fields. The new polarizable force field that employs a modified Buckingham potential predicts the tested properties for gas, liquid and solid phases with a very good accuracy. In contrast to reference force fields, this model reproduces the correct crystal structures for all alkali halides at low and high temperature. Seeing that experiments with molten salts may be tedious due to high temperatures and their corrosive nature, the models presented here can contribute significantly to our understanding of alkali halides in general and melts in particular.

Many attempts have been made to find hints explaining the relationship between physicochemical and structural properties of antimicrobial peptides (AMPs) which are relevant to their antimicrobial activities. We here found that there is a difference in the percentages of hydrophobic, hydrophilic, and charged residues between AMPs killing both bacteria and fungi (Group A) and AMPs that only kill bacteria (Group B). The percentage of charged residues in Group A AMPs is highly elevated, while in Group B the percentage of hydrophobic residues is increased. This result suggests a sequence-based mechanism of selectivity for AMPs. Moreover, we examined how the distance between basic residues affects the interaction free energy of AMPs with the membrane surface, since most of the known AMPs act by membrane perturbation. We measured the average distance between basic residues throughout the 3D structure of AMPs by defining Dpr parameter and calculated the interaction free energy for 10 AMPs that interacted with the DPPC membrane using molecular dynamics simulation. We found that the changes of the interaction free energy correlates with the change of Dpr by a linear regression coefficient of r(2 )= .47 and a cubic regression coefficient of r(2 )= .70.

Large scale quantum calculations for molar enthalpy of formation (Delta(f) H-0), standard entropy (S-0), and heat capacity (C-V) are presented. A large data set may help to evaluate quantum thermochemistry tools in order to uncover possible hidden shortcomings and also to find experimental data that might need to be reinvestigated, indeed we list and annotate approximately 200 problematic thermochemistry measurements. Quantum methods systematically underestimate S-0 for flexible molecules in the gas phase if only a single (minimum energy) conformation is taken into account. This problem can be tackled in principle by performing thermochemistry calculations for all stable conformations [Zheng et al., Phys. Chem. Chem. Phys. 13, 10885-10907 (2011)], but this is not practical for large molecules. We observe that the deviation of composite quantum thermochemistry recipes from experimental S-0 corresponds roughly to the Boltzmann equation (S = R ln Omega), where R is the gas constant and Omega the number of possible conformations. This allows an empirical correction of the calculated entropy for molecules with multiple conformations. With the correction we find an RMSD from experiment of approximate to 13 J/mol K for 1273 compounds. This paper also provides predictions of Delta(f) H-0, S-0, and C-V for well over 700 compounds for which no experimental data could be found in the literature. Finally, in order to facilitate the analysis of thermodynamics properties by others we have implemented a new tool obthermo in the OpenBabel program suite [O'Boyle et al., J. Cheminf. 3, 33 (2011)] including a table of reference atomization energy values for popular thermochemistry methods.

Phytase efficiently catalyzes the hydrolysis of phytate to phosphate; it can be utilized as an animal supplement to provide animals their nutrient requirements for phosphate and to mitigate environmental pollution caused by unutilized feed phosphate. Owing to animal feed being commonly pelleted at 70 to 90 °C, phytase with a sufficiently high thermal stability is desirable. Based on the crystal structure of PhyA and bioinformatics analysis at variant heat treatments, 12 single and multiple mutants were introduced by site-directed mutagenesis in order to improve phytase thermostability. Mutated constructs were expressed in Pichia pastoris. The manipulated phytases were purified; their biochemical and kinetic investigation revealed that while the thermostability of six mutants was improved, P9 (T314S Q315R V62N) and P12 (S205N S206A T151A T314S Q315R) showed the highest heat stability (P < 0.05) with 24 and 22.6 % greater retention, respectively, compared with the PhyA of the wild type at 80 °C. The K m value of the improved thermostable P9 and P12 mutant enzymes for sodium phytate were 35 and 20 % lower (P < 0.05) with respect to the wild-type enzyme. In conclusion, it is feasible to simultaneously improve the thermostability and the catalytic efficiency of phytase to be used as an animal feed supplement.

Motivation: Molecular dynamics (MD) simulations have had a profound impact on studies of membrane proteins during past two decades, but the accuracy of MD simulations of membranes is limited by the quality of membrane models and the applied force fields. Membrane models used in MD simulations mostly contain one kind of lipid molecule. This is far from reality, for biological membranes always contain more than one kind of lipid molecule. Moreover, the lipid composition and their distribution are functionally important. As a result, there is a necessity to prepare more realistic lipid membranes containing different types of lipids at physiological concentrations. Results: To automate and simplify the building process of heterogeneous lipid bilayers as well as providing molecular topologies for included lipids based on both united and all-atom force fields, we provided MemBuilder as a web-based graphical user interface. Availability and implementation: MemBuilder is a free web server available from www.membuilder.org. Contact: sh.arab@modares.ac.ir

Plasma membrane of each micro-organism has a unique set of lipid composition as a consequence of the environmental adaptation or a response to exposure to antimicrobial peptides (AMPs) as antibiotic agents. Understanding the relationship between lipid composition and action of antimicrobial peptides or considering how different lipid bilayers respond to AMPs may help us design more effective peptide drugs in the future. In this contribution, we intend to elucidate how two currently used membrane models, namely palmitoyl-oleoyl-phosphtidylglycerol (POPG) and 1-palmitoyl-oleoyl-glycero-phosphocholine (POPC), respond to antimicrobial peptide Piscidin-1 (Pis-1).The computed density profile of the peptide as it moves from the bulk solvent toward the membrane core suggests that Pis-1 penetrates into the POPG bilayer less than the POPC membrane. Furthermore, we showed that the two model membranes used in this study have different behavior in the presence of Pis-1. Hence, we suggest that membrane composition could be an important factor in determining lytic ability of peptide drugs to kill a unique bacterial species.

Co-solvents such as glycerol and sorbitol are small organic molecules solvated in the cellular solutions that can have profound effects on the protein structures. Here, the molecular dynamics simulations and comparative structural analysis of magainin, as a peptide model, in pure water, 2,2,2-trifluoroethanol/water, glycerol/water, and sorbitol/water are reported. Our results show that the peptide NMR structure is largely maintained its native structure in osmolytes–water mixtures. The simulation data indicates that the stabilizing effect of glycerol and sorbitol is induced by preferential accumulation of glycerol and sorbitol molecules around the nonpolar and aromatic residues. Thus, the presence of glycerol and sorbitol molecules decreases the interactions of water molecules with the hydrophobic residues of the peptide, and the alpha helical structure is stabilized.

Since neurotransmitter releasing into the synaptic space delivers electrical signals from presynaptic neural cell to the postsynaptic cell, neurotransmitter secretion must be much orchestrated. Crowded intracellular vesicles involving neurotransmitters present a question of the how secretory vesicles fuse onto the plasma membrane in a fast synchronized fashion. Complexin is one of the most experimentally studied proteins that regulate assembly of fusogenic four-helix SNARE complex to synchronized neurotransmitter secretion. We used MD simulation to investigate the interaction of complexin with the neural SNARE complex in detail. Our results show that the SNARE complex interacts with the complexin central helix by forming salt bridges and hydrogen bonds. Complexin also can interact with the Q-SNARE complex instead of synaptobrevin to decrease the Q-SNARE flexibility. The complexin alpha-accessory helix and the C-terminal region of synaptobrevin can interact with the same region of syntaxin. Although the alpha-accessory helix aids the tight binding of the central helix to the SNARE complex, its proximity with synaptobrevin causes the destabilization of syntaxin and Sn1 helices. This study suggests that the alpha-accessory helix of complexin can be an inhibiting factor for membrane fusion by competing with synaptobrevin for binding to the Q-SNARE complex.