Force Field Calculations Research Articles

Adjusting the Energy Profile for CH-O Interactions Leads to Improved Stability of RNA Stem-Loop Structures in MD Simulations.

The role of ribonucleic acid (RNA) in biology continues to grow, but insight into important aspects of RNA behavior is lacking, such as dynamic structural ensembles in different environments, how flexibility is coupled to function, and how function might be modulated by small molecule binding. In the case of proteins, much progress in these areas has been made by complementing experiments with atomistic simulations, but RNA simulation methods and force fields are less mature. It remains challenging to generate stable RNA simulations, even for small systems where well-defined, thermostable structures have been established by experiments. Many different aspects of RNA energetics have been adjusted in force fields, seeking improvements that are transferable across a variety of RNA structural motifs. In this work, the role of weak CH···O interactions is explored, which are ubiquitous in RNA structure but have received less attention in RNA force field development. By comparing data extracted from high-resolution RNA crystal structures to energy profiles from quantum mechanics and force field calculations, it is shown that CH···O interactions are overly repulsive in the widely used Amber RNA force fields. A simple, targeted adjustment of CH···O repulsion that leaves the remainder of the force field unchanged was developed. Then, the standard and modified force fields were tested using molecular dynamics (MD) simulations with explicit water and salt, amassing over 300 μs of data for multiple RNA systems containing important features such as the presence of loops, base stacking interactions as well as canonical and noncanonical base pairing. In this work and others, standard force fields lead to reproducible unfolding of the NMR-based structures. Including a targeted CH···O adjustment in an otherwise identical protocol dramatically improves the outcome, leading to stable simulations for all RNA systems tested.

Design of Novel Membranes for the Efficient Separation of Bee Alarm Pheromones in Portable Membrane Inlet Mass Spectrometric Systems.

Bee alarm pheromones are essential molecules that are present in beehives when some threats occur in the bee population. In this work, we have applied multilevel modeling techniques to understand molecular interactions between representative bee alarm pheromones and polymers such as polymethyl siloxane (PDMS), polyethylene glycol (PEG), and their blend. This study aimed to check how these interactions can be manipulated to enable efficient separation of bee alarm pheromones in portable membrane inlet mass spectrometric (MIMS) systems using new membranes. The study involved the application of powerful computational atomistic methods based on a combination of modern semiempirical (GFN2-xTB), first principles (DFT), and force-field calculations. As a fundamental work material for the separation of molecules, we considered the PDMS polymer, a well-known sorbent material known to be applicable for light polar molecules. To improve its applicability as a sorbent material for heavier polar molecules, we considered two main factors-temperature and the addition of PEG polymer. Additional insights into molecular interactions were obtained by studying intrinsic reactive properties and noncovalent interactions between bee alarm pheromones and PDMS and PEG polymer chains.

Enhancing the Catalytic Efficiency of D-lactonohydrolase through the Synergy of Tunnel Engineering, Evolutionary Analysis, and Force-Field Calculations.

Computational design advances enzyme evolution and their use in biocatalysis in a faster and more efficient manner. In this study, a synergistic approach integrating tunnel engineering, evolutionary analysis, and force-field calculations has been employed to enhance the catalytic activity of D-lactonohydrolase (D-Lac), which is a pivotal enzyme involved in the resolution of racemic pantolactone during the production of vitamin B5. The best mutant, N96S/A271E/F274Y/F308G (M3), was obtained and its catalytic efficiency (kcat/KM) was nearly 23-fold higher than that of the wild-type. The M3 whole-cell converted 20 % of DL-pantolactone into D-pantoic acid (D-PA, >99 % e.e.) with a conversion rate of 47 % and space-time yield of 107.1 g L-1 h-1, demonstrating its great potential for industrial-scale D-pantothenic acid production. Molecular dynamics (MD) simulations revealed that the reduction in the steric hindrance within the substrate tunnel and conformational reconstruction of the distal loop resulted in a more favourable"catalytic" conformation, making it easier for the substrate and enzyme to enter their pre-reaction state. This study illustrates the potential of the distal residue on the pivotal loop at the entrance of the D-Lac substrate tunnel as a novel modification hotspot capable of reshaping energy patterns and consequently influencing the enzymatic activity.

Molecular islands at the liquid-solid interface.

Molecular islands of various shapes and sizes composed of a few tens of molecules only are formed at the liquid-solid interface, at room temperature, by an alkoxylated dehydrobenzo[12]annulene (DBA) derivative. Molecules are packed into hexagons. Scanning tunneling microscopy reveals the variety in molecular island structures and their stability. For molecular islands up to 7 hexagonal pores, all 244 possible structures are simulated and compared with experimental observations. Force field calculations give insights into the relative stability of the molecular islands and the factors contributing to it.

Reinvestigation of the ν3-ν6 Coriolis interaction in trifluoroiodomethane.

The lowest-frequency fundamental ν6 of trifluoroiodomethane (CF3I) has never been directly observed and analyzed at high resolution in the gas phase. The ν6(e) level interacts with ν3(a1) at 286.297 cm-1via a b-axis Coriolis interaction, which perturbs the rotational structure of both levels. In this work, we report low-J microwave transitions (for J ranging from 0-2) within the ν6 vibrational level. The l-type doubling observed in our spectrum agreed poorly with the predictions of previously published models of the interacting ν3-ν6 levels, prompting us to refine the model. We performed ab initio anharmonic force-field calculations, which were used to constrain some of the parameters, and which served as a check on some of the floated parameters. We fit a dataset consisting of 3593 transitions, which combined our measurements with previous microwave, millimeter wave, and high-resolution infrared observations. A reasonable set of fit parameters is obtained with ν6 = 267.28 cm-1, but we cannot rule out a lower value of ν6 = 261.5 cm-1 consistent with analyses of the vibrational level structure.

Force Field for Calculation of the Vapor-Liquid Phase Equilibrium of trans-Decalin

Based on the TraPPE force field, previously unknown values of the parameters of the intermolecular interaction potential of trans-decalin were determined. Parametrization was carried out using experimental data on saturated vapor pressure and density at atmospheric pressure. The found parameters make it possible to adequately describe the boiling and condensation lines of trans-decalin and also predict the critical values of pressure, density, and temperature with satisfactory accuracy. Calculations of vapor-liquid phase equilibrium conditions for a binary CO2—trans-decalin mixture in supercritical conditions for CO2 were carried out. When quantitatively comparing the calculated values with experimental data, an underestimation of pressure at a temperature of 345.4 K by 30% is observed, which decreases to 5% for temperatures up to 525 K.

Structural, spectroscopic and second harmonic generation evaluation of 1,2,4-triazolinium tartrate - tartaric acid as a promising nonlinear optical material

Crystallization of 1,2,4-triazole with (2R,3R)-(+)-tartaric acid (l (+)-tartaric acid) in a 1:2 ratio yields the ionic co-crystals of 1,2,4-triazolium tartrate – tartaric acid (1:1), (C2H4N3) (C4H5O6)‧C4H6O6 – (abbreviated as TATT). TATT crystallizes in the tetragonal system with a non-centrosymmetric P41212 space group of eight molecules per unit cell. Apart from ionic interaction by the building ions and N–H‧‧‧O, the 1,2,4-triazolinium cation and the tartrate anion interact through hydrogen bonds and O–H‧‧‧O with tartaric acid to form a supramolecular complex (C2H4N3) (C4H5O6)‧C4H6O6 (TATT). Hydrogen bonds further organise these supramolecular complexes into a three-dimensional network. The interactions between the building blocks of the co-crystal were analyzed using Hirshfeld surface and 2D fingerprint plots. Normal coordinate force field calculations based on density functional theory (DFT) and structure optimizations were utilized to interpret the molecular structure and fundamental vibrational frequencies. The wave numbers' complete vibrational assignments were determined through potential energy distribution (PED). The HOMO and LUMO energy gap calculations explained the charge transfer interactions within the supramolecular unit. For the TATT co-crystal, the efficiency of the second harmonic generation (SHG) process was investigated under 800 nm irradiation using the Kurtz–Perry powder technique. The ionic co-crystal demonstrated a low SHG efficiency on the order of 10−1 compared to that of KDP.

Vibrational assignments of cyclic dimers and inter-monomers of adenine relating FT-IR, FT-Raman and UV spectra with SQMFF and DFT calculations

In this work, three different cyclic dimers and a tetramer of adenine taken from the experimental structure determined by X-ray diffraction have been studied by combination of experimental FT-IR, FT-Raman and UV–Visible spectra with hybrid B3LYP/6–311++G** and scaled quantum mechanical force field (SQMFF) calculations in order to perform the complete assignments of bands observed in the vibrational spectra. The characteristics of different N-H···N interactions of those three cyclic structures together with the group of IR bands observed between 2865 and 2599 cm−1 have been elucidated considering the tetrameric structure. The cyclic dimers and the tetramer of adenine confirm that the bands observed between 2865 and 2599 cm−1 are not due to N-H···N interactions but to bands of combination, as was previously suggested. The experimental available deuterated IR and terahertz spectra have allowed the complete assignments of regions of higher and lower wavenumbers. Good correlations were acquired comparing the theoretical IR, Raman and UV spectra of three species and the tetramer with the analogous experimental ones, suggesting the presence of all species in both phases. Vibronic bands are observed in the electronic spectra when adenine concentration is increased in aqueous solution evidencing the presence of monomer, tautomers and dimers, as reported by different studies. Similar characteristics of H bonds interactions are predicted for dimers 1 and 2 but different from the dimer 3, as revealed by using NBO and AIM calculations. Different scaled force constants values were found for the cyclic dimers 1 and 2, as compared to the corresponding to dimer 3.

Advancing Enzyme's Stability and Catalytic Efficiency through Synergy of Force-Field Calculations, Evolutionary Analysis, and Machine Learning.

Thermostability is an essential requirement for the use of enzymes in the bioindustry. Here, we compare different protein stabilization strategies using a challenging target, a stable haloalkane dehalogenase DhaA115. We observe better performance of automated stabilization platforms FireProt and PROSS in designing multiple-point mutations over the introduction of disulfide bonds and strengthening the intra- and the inter-domain contacts by in silico saturation mutagenesis. We reveal that the performance of automated stabilization platforms was still compromised due to the introduction of some destabilizing mutations. Notably, we show that their prediction accuracy can be improved by applying manual curation or machine learning for the removal of potentially destabilizing mutations, yielding highly stable haloalkane dehalogenases with enhanced catalytic properties. A comparison of crystallographic structures revealed that current stabilization rounds were not accompanied by large backbone re-arrangements previously observed during the engineering stability of DhaA115. Stabilization was achieved by improving local contacts including protein-water interactions. Our study provides guidance for further improvement of automated structure-based computational tools for protein stabilization.

Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors.

Kallikrein 6 (KLK6) is an attractive drug target for the treatment of neurological diseases and for various cancers. Herein, we explore the accuracy and efficiency of different computational methods and protocols to predict the free energy of binding (ΔGbind) for a series of 49 inhibitors of KLK6. We found that the performance of the methods varied strongly with the tested system. For only one of the three KLK6 datasets, the docking scores obtained with rDock were in good agreement (R2 ≥ 0.5) with experimental values of ΔGbind. A similar result was obtained with MM/GBSA (using the ff14SB force field) calculations based on single minimized structures. Improved binding affinity predictions were obtained with the free energy perturbation (FEP) method, with an overall MUE and RMSE of 0.53 and 0.68kcal/mol, respectively. Furthermore, in a simulation of a real-world drug discovery project, FEP was able to rank the most potent compounds at the top of the list. These results indicate that FEP can be a promising tool for the structure-based optimization of KLK6 inhibitors.

Clustering of caffeine in water and its adsorption in activated carbon: Molecular simulations and experiments

Motivated by the importance of caffeine removal from wastewater, the clustering and adsorption of caffeine in activated carbon are studied using Molecular Dynamics and Grand Canonical Monte Carlo simulations, and the results validated by experiments showing similar clustering mechanisms in the large pores as well as high caffeine concentrations in water. The mechanism of caffeine clustering as a function of concentration from high concentration up to solubility threshold is described by the creation of hydrogen bonds between dimers (hydrogen of methyl group and oxygen of caffeine) and between dimers and another caffeine molecule (hydrogen bonds between the hydrogen of methyl group and nitrogen of another caffeine molecule). The caffeine solvation pattern shows strong interaction between water and nitrogen atoms of the caffeine molecule. Analysis of the unfolding of caffeine aggregates shows that the solvent accessible surface area varies from 120 to 350 Å2/caffeine molecule (solvent accessible surface area of a single caffeine molecule). Caffeine dimers and more complex forms are also observed in the GCMC simulations, and show that the same mechanism behind the caffeine clustering produces caffeine stacks in the large pores of nanoporous carbon (Activated Carbon Cloth (ACC)). For all molecular simulations, we have utilized our new computed force field for the caffeine molecule as the most accurate force field for both MD and GCMC. This new force field is examined by neutron scattering experiments in the literature for MD simulations and by adsorption isotherm and X-ray scattering experiments for GCMC simulations. According to the X-ray intensity measurements on ACC before and after adsorption, and molecular simulation results, we conclude that this new force field is more accurate than similar force fields in the literature as it produces satisfactory results for both MD and GCMC simulations.

Deep ensembles vs committees for uncertainty estimation in neural-network force fields: Comparison and application to active learning.

A reliable uncertainty estimator is a key ingredient in the successful use of machine-learning force fields for predictive calculations. Important considerations are correlation with error, overhead during training and inference, and efficient workflows to systematically improve the force field. However, in the case of neural-network force fields, simple committees are often the only option considered due to their easy implementation. Here, we present a generalization of the deep-ensemble design based on multiheaded neural networks and a heteroscedastic loss. It can efficiently deal with uncertainties in both energy and forces and take sources of aleatoric uncertainty affecting the training data into account. We compare uncertainty metrics based on deep ensembles, committees, and bootstrap-aggregation ensembles using data for an ionic liquid and a perovskite surface. We demonstrate an adversarial approach to active learning to efficiently and progressively refine the force fields. That active learning workflow is realistically possible thanks to exceptionally fast training enabled by residual learning and a nonlinear learned optimizer.

Is imogolite a suitable adsorbent agent for the herbicides like diuron and atrazine?

Nanotubular minerals are gained researchers’ interest for environmental applications and their use as adsorbents due to their structural characteristics. Imogolite mineral belongs to aluminosilicates and can be characterised as a promising sorbent due to its abundant nature as it has both natural and synthetic origins. In the present study, the potential interactions of imogolite mineral with the herbicides diuron and atrazine have been investigated via theoretical approaches to characterise the mineral as a potential adsorbent for water or soil treatment applications. Force Field calculations showed stronger interactions between imogolite outer surface and herbicides. Diuron molecules had a better adaptation to the nanotubular shape by torsion, unlike atrazine molecules, when herbicides interacted with the inner surface due to their molecule length and rigidity. The release of the herbicides from the imogolite nanotube showed the unstable nature of both herbicides when they were loaded on the inner part of imogolite, which is in agreement with the sorption studies that proved the preference for herbicides on the outer surface and the edges of the minerals. Water molecules played a crucial role in the complexes related to imogolite properties as its inner surface is more hydrophilic. When herbicides were loaded on the outer surface, water molecules were the intermediate medium for the sorption of herbicides creating hydrogen bonds. In contrast, on the inner surface, the herbicide molecules had a competed behaviour to water. From a theoretical point of view, imogolite is a feasible sorbent for herbicides, especially when loaded on the mineral's outer part, creating high stability of complexes.

Structural and Mechanistic Studies on Substrate and Stereoselectivity of the Indole Monooxygenase VpIndA1: New Avenues for Biocatalytic Epoxidations and Sulfoxidations.

Flavoprotein monooxygenases are a versatile group of enzymes for biocatalytic transformations. Among these, group E monooxygenases (GEMs) catalyze enantioselective epoxidation and sulfoxidation reactions. Here, we describe the crystal structure of an indole monooxygenase from the bacterium Variovorax paradoxus EPS, a GEM designated as VpIndA1. Complex structures with substrates reveal productive binding modes that, in conjunction with force-field calculations and rapid mixing kinetics, reveal the structural basis of substrate and stereoselectivity. Structure-based redesign of the substrate cavity yielded variants with new substrate selectivity (for sulfoxidation of benzyl phenyl sulfide) or with greatly enhanced stereoselectivity (from 35.1 % to 99.8 % ee for production of (1S,2R)-indene oxide). This first determination of the substrate binding mode of GEMs combined with structure-function relationships opens the door for structure-based design of these powerful biocatalysts.

STM Study of the Self-Assembly of Biphenyl-3,3′,5,5′-Tetracarboxylic Acid and Its Mixing Behavior with Coronene at the Liquid–Solid Interface

We report a scanning tunneling microscopy (STM) study of the molecular self-assembly of biphenyl-3,3',5,5'-tetracarboxylic acid (BPTC) at the octanoic acid/graphite interface. STM revealed that the BPTC molecules generated stable bilayers and monolayers under high and low sample concentrations, respectively. Besides hydrogen bonds, the bilayers were stabilized by molecular π-stacking, whereas the monolayers were maintained by solvent co-adsorption. A thermodynamically stable Kagomé structure was obtained upon mixing BPTC with coronene (COR), while kinetic trapping of COR in the co-crystal structure was found by the subsequent deposition of COR onto a preformed BPTC bilayer on the surface. Force field calculation was conducted to compare the binding energies of different phases, which helped to provide plausible explanations for the structural stability formed via kinetic and thermodynamic pathways.

Molecular structure and spectroscopic properties of two radicals of C4H2N: a DFT study.

The cyano propargyl radical (CH2C3N and HC3HCN) is important reaction intermediate in both combustion flames and extraterrestrial environments such as cold molecular clouds and circumstellar envelopes of carbon stars. The acquisition of spectroscopic constants and anharmonic effect facilitates a more in-depth study of this radical. However, the data available in the literature do not allow the precise predictions for it in the interstellar medium. In this work, complete spectroscopic parameters as well as anharmonic constants of two radicals of C4H2N have been evaluated by different DFT methods. The calculated results show that it is reasonable to study the molecular spectroscopic properties of C4H2N by wB97XD/6-311++G theoretical level. On this basis, the sextic centrifugal distortion constants, anharmonic constants, vibration-rotation interaction constants, and so on are predicted for the study of high-precision rovibrational spectrum. In addition, the relationship between the anharmonic effect and vibration mode of CH2C3N and HC3HCN and their infrared spectroscopic characteristics are discussed. The calculation of the anharmonic force fields and spectroscopy properties was performed using B3LYP, B3PW91, CAM-B3LYP, and wB97XD methods combined with the 6-311++G and aug-ccpVTZ basis sets, respectively, by the Gaussian16 program suite. The IR spectra were performed with Multiwfn3.8.

Conformational Diversity in Partially Fluorinated N‐Alkyl Pipecolic Acid Amide Derivatives

AbstractThe molecular and crystal structures of 19 N‐alkyl‐substituted pipecolamide derivatives with partial fluorination of N‐propyl and N‐butyl groups are presented. Fluorination patterns include one F‐atom at internal or terminal locations, two F‐atoms in geminal or vicinal arrangements at various positions, as well as terminal trifluoromethylation. Due to the presence of the carboxamide side chain in pipecolamide derivatives, enantiomeric fluorination patterns in the N‐alkyl group result in diastereomeric compounds, which exhibit dramatically different crystal and molecular structures. An extraordinary conformational diversity is diagnosed for the various N‐alkylpiperidine units. Structural comparisons and theoretical assessments based on extensive force field calculations provide insight into consistent conformational patterns that point to intramolecular factors as well as intermolecular modulations due to crystal packing effects.

Thermodynamic Morphological Study of Liquid Crystalline Compounds

Thermodynamic morphism study has been envisaged using search procedure of phase space of polymorphs at a prescribed temperature and pressure(NPT) of several azoxybenzenes based liquid crystalline compounds at room temperature using molecular structure, unit cell information and AMOEBA parameters employing Force Field computation (FFX) calculations. These calculations were carried out at various intermolecular strengths to understand the morphological walk of molecules with corresponding changes in free energy, change in a force field with a strength of the interactions and free energy difference between successive interaction strengths. This study will help us to understand the nature, range and type of mesophase in a series of azoxybenzene compounds.

Structure and bonding in cryolitic melts a combined study by density functional theory and ionic model calculations

Present study aims to analyze the nature of the bonding of ion pairs and formation of Al(III) fluorocomplexes by discussing the detailed ion pair interactions for various microclusters on AlF3/NaF solutions (cryolitic melts). Using a comparative study between the density functional theory and an interionic force-field model calculations developed in our group, the structure of neutral micro clusters in cryolitic melts are analyzed to reveal their bonding characteristics of the ion pairs. Quantum Theory of Atoms in Molecules (QTAIM) analyses were perfomed in order to understand the molecular or ionic interactions both in vacuo and in dielectric continuum. This study provides detailed information about the local structure in cryolitic melts in terms of the bonding interactions between the ions.

Theoretical Study on the Vapochromic Ni(II)-Quinonoid Complex: One-Dimensional Stacking Structure-Based Color Switching.

Vapochromic crystals of Ni(II)-quinonoid complexes were theoretically investigated using density functional theory (DFT) calculations. Kato et al. previously reported that the purple crystals of a four-coordinate Ni(II)-quinonoid complex (1P) exhibited vapochromic characteristics upon exposure to methanol gas, resulting in orange crystals of the six-coordinate methanol-bound complex (1O) [Angew. Chem., Int. Ed.2017, 56, 2345-2349]. However, the authors did not characterize the crystal structure of 1P. In the present study, we computationally predicted the crystal structure of 1P by performing a crystal structure search with classical force-field computations followed by optimization using DFT calculations. The simulated powder X-ray diffraction pattern of the DFT-optimized structure agreed with experimental observations, indicating that our predicted crystal structure is reliable. Investigation of the optimized crystal structure of 1P revealed that its color change arose from changes in its 1D-band structure, which consists of Ni 3d orbitals and quinonoid π-orbitals. Intermolecular interactions were weakened upon the binding of methanol to the Ni(II) center in 1O. Consequently, the intermolecular 3d-π interaction in 1P lowered the band gap and induced the red-shifting of the monomeric four-coordinate Ni(II)-quinonoid complex. Meanwhile, the obtained absorption spectrum of 1O closely corresponded to that of the monomeric six-coordinate Ni(II)-quinonoid complex. Our study provides a new strategy for accurately predicting molecular crystal structures and reveals a new insight into vapochromism based on band structure color switching.