AMBER Force Field Research Articles

Block Chemistry for Accurate Modeling of Epoxy Resins.

Accurate molecular modeling of the physical and chemical behavior of highly cross-linked epoxy resins at the atomistic scale is important for the design of new property-optimized materials. However, a systematic approach to parametrizing and characterizing these systems in molecular dynamics is missing. We therefore present a unified scheme to derive atomic charges for amine-based epoxy resins, in agreement with the AMBER force field, based on defining reactive fragments─blocks─building the network. The approach is applicable to all stages of curing from pure liquid to gelation to fully cured glass. We utilize this approach to study DGEBA/DDS epoxy systems, incorporating dynamic topology changes into atomistic molecular dynamics simulations of the curing reaction with 127,000 atoms. We study size effects in our simulations and predict the gel point utilizing a rigorous percolation theory to recover accurately the experimental data. Furthermore, we observe excellent agreement between the estimated and the experimentally determined glass transition temperatures as a function of curing rate. Finally, we demonstrate the quality of our model by the prediction of the elastic modulus based on uniaxial tensile tests. The presented scheme paves the way for a broadly consistent approach for modeling and characterizing all amine-based epoxy resins.

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the FreeSolv database (621 out of 642). The force field parameters were obtained with the program cgenff (v2.5.1), which derives missing parameters from the CHARMM general force field (CGenFF v4.6). A long-range correction for the Lennard-Jones interactions was added to all computed solvation free energies. The mean absolute error compared to the experimental data is 1.12 kcal/mol. Our results allow a detailed comparison between the AMBER and CHARMM general force fields and provide a more in-depth understanding of the capabilities and limitations of the CGenFF small molecule parameters.

Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)2Cl]

The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, the vanadium complex (VC) bis(2,2'-bipyridine)chlorooxovanadium(IV), [VO(bpy)2Cl], is known for its ability to induce autophagy in triple-negative breast cancer cells (TNBC). An excellent resource to investigate the role of VC in the induction of autophagy is to make use of Molecular Dynamics (MD) simulations. However, until now, the scarcity of force field parameters for the VC prevented a reliable analysis. The autophagy signaling pathway starts with the PI3K protein and ends with ULK1. Therefore, in the first stage of this work, we developed a new AMBER force field for the VC (VCFF) from a quantum structure, obtained by DFT calculations. In the second stage, the VCFF was validated through structural analyses. From this, it was possible to investigate, through docking and MD (200 ns), the performance of the PI3K-VC and ULK1-VC systems (third stage). The analyses of this last stage involved RMSD, hydrogen bonds, RMSF and two pathways for the modulation of autophagy. In general, this work fills in the absence of force field parameters (FF) for VC by proposing an efficient and new FF, in addition to investigating, at the molecular level, how VC is able to induce autophagy in TNBC cells. This study encourages new parameterizations of metallic complexes and contributes to the understanding of the duality of autophagic processes. Communicated by Ramaswamy H. Sarma

Uridylation of the histone mRNA stem-loop weakens binding interactions with SLBP while maintaining interactions with 3’hExo

ABSTRACT Histone mRNA degradation is controlled by the unique 3’ stem-loop of histone mRNA and the stem-loop binding protein (SLBP). As part of this process, the 3’ stem-loop is trimmed by the histone-specific 3’ exonuclease (3’hExo) and uridylated by the terminal uridylyl transferase 7 (TUT7), creating partially degraded intermediates with short uridylations. The role of these uridylations in degradation is not fully understood. Our work examines changes in the stability of the ternary complex created by trimming and uridylation of the stem-loop to better understand the role of this process in the histone mRNA life cycle. In this study, we used fluorescence polarization and electrophoretic mobility shift assays to demonstrate that both SLBP and 3’hExo can bind to uridylated and partially degraded stem-loop intermediates, although with lower affinity. We further characterized this complex by performing 1-µs molecular dynamics simulations using the AMBER force field and Nanoscale Molecular Dynamics (NAMD). These simulations show that while uridylation helps maintain the overall shape of the stem-loop, the combination of uridylation and dephosphorylation of the TPNK motif in SLBP disrupts key RNA–protein interactions. They also demonstrate that uridylation allows 3’hExo to maintain contact with the stem-loop after partial degradation and plays a role in disrupting key base pairs in partially degraded histone mRNA intermediates. Together, these experiments and simulations suggest that trimming by 3’hExo, uridylation, and SLBP dephosphorylation weakens both RNA–protein interactions and the stem-loop itself. Our results further elucidate the role of uridylation and SLBP dephosphorylation in the early stages of histone mRNA degradation.

Molecular Docking and Dynamics of SARS-CoV-2 Programmed Ribosomal Frameshifting RNA and Ligands for RNA-Targeting Alkaloids Prospecting

RNA-ligand docking is a part of computational biology, which is currently lowly recognized compared to the protein-ligand docking procedure commonly applied for drug discovery. This in silico study aims to create a simplified protocol for RNA-ligand docking, which is applicable to RNA-targeting small molecular drug screening. Four alkaloids (berberine, colchicine, nicotine, and tomatine) were subjected to this study and contended against the SARS-CoV-2 genomic RNA -1 PRF component targeting control drug, merafloxacin, including two known intercalator berberine and colchicine, a small alkaloid nicotine and a large alkaloid tomatine. The alkaloids were screened for drug-likeness properties (Lipinski’s Rules of 5 or LRo5), bioavailability indexes, and synthetic accessibility values using SwissADME before docking. The docking used PyRx – Autodock Vina and re-scored for RNA-ligand scoring using AnnapuRNA. The docking results have the interactions mapped using fingeRNAt and visualized using Discovery Studio. Molecular dynamics using CHARMM36 and AMBER forcefields were simulated in NAMD. The molecular dynamics 1 ns simulation results showed that the ligand interaction over time did not cause much interference with the RNA, indicated by the low number of RMSD changes between RNA itself and the RNA-ligand complex. Additionally, CHARMM36 forcefield provided more stable fluctuation compared to AMBER. The results indicated that tomatine disobeyed LRo5 and had a low bioavailability index and bad synthetic accessibility value, while the rest alkaloids passed. In the end, berberine has an even higher docking score than the control drug. The study also shows that this protocol can be useful for future RNA-ligand computational studies.

Interfaces in reinforced epoxy resins: from molecular scale understanding towards mechanical properties

ContextWe report on atomic level of detail analyses of polymer composite models featuring epoxy resin interfaces to silica, iron oxide, and cellulose layers. Using “reactive” molecular dynamics simulations to explore epoxy network formation, resin hardening is investigated in an unprejudiced manner. This allows the detailed characterization of salt-bridges and hydrogen bonds at the interfaces. Moreover, our sandwich-type composite systems are subjected to tensile testing along the interface normal. To elucidate the role of relaxation processes, we contrast (i) direct dissociation of the epoxy-metal oxide/cellulose contact layer, (ii) constant strain-rate molecular dynamics studies featuring (visco-)elastic deformation and bond rupture of the epoxy resin, and (iii) extrapolated relaxation dynamics mimicking quasi-static conditions. While the fracture mechanism is clearly identified as interface dissociation of the composite constituents, we still find damaging of the nearby polymer phase. The observed plastic deformation and local cavitation are rationalized from the comparably large stress required for the dissociation of salt-bridges, hydrogen bonds, and van der Waals contacts. Indeed, the delamination of the contact layers of epoxy resins with slabs of silica, magnetite, and cellulose call for a maximum stress of 33, 26, and 21 MPa, respectively, as compared to 84 MPa required for bulk epoxy yielding.MethodsMolecular dynamics simulations using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) code were augmented by a Monte Carlo–type procedure to probe epoxy bond formation (Macromolecules 53(22): 9698–9705). The underlying interaction models are split into conventional Generalized Amber Force Fields (GAFF) for non-reacting moieties and a recently developed reactive molecular mechanics potential enabling epoxy bond formation and cleavage (ACS Polymers Au 1(3): 165–174).

In-silico structural studies on anti-inflammatory activity of phytocompounds from the genus Andrographis

Plant species from the genus Andrographis were used in Ayurveda and in other folklore medicines for treating ailments for centuries. In this study, we have hypothesized to evaluate the secondary metabolites as potent anti-inflammatory agents from the genus Andrographis. A library of secondary metabolites of the said genus was curated from the PubChem database and was subjected to energy minimization using UCSF Chimera software employing the AMBER force field. Initially, molecular docking was performed to evaluate the binding affinity of the curated library against the enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-Lipoxygenase (5-LOX) using AutoDock Vina. This resulted in shortlisting of two metabolites Echioidinin 5-O-glucoside was bound and 5,2',6'-Trihydroxy-6,7,8-trimethoxy flavone 2'-O-glucoside with high binding affinity than standard drugs Ibuprofen and Zileuton. In addition, molecular dynamic simulation studies confirm that these compounds form relatively more stable complexes than standard drugs with the above-said enzymes. The free binding energy values using MMGBSA of the above said ligands with COX-1, COX-2, and 5-LOX were found to be −49.18 kcal/mol, −38.60 kcal/mol, and −54.27 kcal/mol respectively, Whereas the standards have −21.77 kcal/mol, −9.96 kcal/mol, and −10.29 kcal/mol. Moreover, the in-silico ADMET analysis confirms the druggability of the shortlisted compounds. Later, this work will act as a base for in-vitro and in-vivo experimental studies to validate the anti-inflammatory potential of the same. Communicated by Ramaswamy H. Sarma

New approach for modeling randomly distributed CNT reinforced polymer nanocomposite with van der Waals interactions

This paper presents a new approach for the prediction of the stiffness of randomly distributed CNT/polymer nanocomposites using molecular and micromechanics methods with the van der Waals (VdW) interactions. A multi-scale modeling technique was designed for CNT nanoparticles randomly embedded in the polymer using an AMBER force field. This multi-scale model constitutes a representative volume element. The representative volume element consists of polymer, CNT nanoparticle, CNT-polymer interfacial region and Van der Waals bonds. A programming code was developed that randomly distributes nanoparticles according to the desired volume fraction. Python scripting language was used for the modeling technique performed in a finite element environment. By modeling the interfacial regions around randomly distributed CNTs, van der Waals bonds are modeled stochastically. In this study, the subject of interest is the number of CNTs positioned in the RVE according to the volume fraction. These numbers were determined at the level allowed by finite element equations and computational solvers and their effects were investigated by calculated stiffness behavior.

Molecular Dynamics Force Field Parameters for the EGFP Chromophore and Some of Its Analogues.

Fluorescent proteins (FPs) have had an enormous impact on molecular and cellular biology and are employed in a wide range of studies of molecular structure and dynamics. Yet, only a modest number of papers have published molecular dynamics (MD) parameters describing FPs. And despite the development of a wide range of FPs, there has been no careful development of MD parameters across a series of FPs. In this work, we present MD parameters describing six fluorescent protein chromophores (EGFP, EBFP, EYFP, ECFP, mCherry, and DsRed) for use with the Cornell et al. ( J. Am. Chem. Soc. 1995, 117, 5179-5197) family of AMBER force fields, including ff14SB and ff19SB. We explore a wide range of solvent dielectric constants for determining the chromophore equilibrium geometry and evaluate the impact of the modeled solvent on the final atomic charges. We also present our methodological approach in which we considered all six chromophores together with a focus on modularity, transferability, and balance with existing force fields. The parameters given here make it easy to employ MD simulations to study any of the six systems, whereas the methodology makes it easy for anyone to extend this work to develop consistent parameters for additional fluorescent proteins. The results of our own MD simulations are presented, showing that the classical MD parameters yield chromophore structural distributions that compare well with QM/MM simulations.

Assessing the Current State of Amber Force Field Modifications for DNA─2023 Edition.

Advances in molecular dynamics (MD) software alongside enhanced computational power and hardware have allowed for MD simulations to significantly expand our knowledge of biomolecular structure, dynamics, and interactions. Furthermore, it has allowed for the extension of conformational sampling times from nanoseconds to the microsecond level and beyond. This has not only made convergence of conformational ensembles through comprehensive sampling possible but consequently exposed deficiencies and allowed the community to overcome limitations in the available force fields. The reproducibility and accuracy of the force fields are imperative in order to produce biologically relevant data. The Amber nucleic acid force fields have been used widely since the mid-1980s, and improvement of these force fields has been a community effort with several artifacts revealed, corrected, and reevaluated by various research groups. Here, we focus on the Amber force fields for use with double-stranded DNA and present the assessment of two recently developed force field parameter sets (OL21 and Tumuc1). Extensive MD simulations were performed with six test systems and two different water models. We observe the improvement of OL21 and Tumuc1 compared to previous generations of the Amber DNA force. We did not detect any significant improvement in the performance of Tumuc1 compared to OL21 despite the reparameterization of bonded force field terms in the former; however, we did note discrepancies in Tumuc1 when modeling Z-DNA sequences.

AMOEBA Force Field Predicts Accurate Hydrogen Bond Counts of Nitriles in SNase by Revealing Water-Protein Interaction in Vibrational Absorption Frequencies.

Precisely quantifying the magnitude and direction of electric fields in proteins has long been an outstanding challenge in understanding biological functions. Nitrile vibrational Stark effect probes have been shown to be minimally disruptive to the protein structure and can be better direct reporters of local electrostatic field in the native state of a protein than other measures such as pKa shifts of titratable residues. However, interpretations of the connection between measured vibrational energy and electric field rely on the accurate molecular understanding of interactions of the nitrile group and its environment, particularly from hydrogen bonding. In this work, we compared the extent of hydrogen bonding calculated in two common force fields, the fixed charge force field Amber03 and polarizable force field AMOEBA, at 10 locations of cyanocysteine (CNC) in staphylococcal nuclease (SNase) against the experimental nitrile absorption frequency in terms of full width at half-maximum (FWHM) and frequency temperature line slope (FTLS). We observed that the number of hydrogen bonds correlated well in AMOEBA trajectories with respect to both the FWHM (r = 0.88) and the FTLS (r = -0.85), whereas the correlation of Amber03 trajectories was less reliable because the Amber03 force field predicted more hydrogen bonds in some mutants. Moreover, we demonstrated that contributions from the interactions between CNC and nearby water molecules were significant in AMOEBA trajectories but were not predicted by Amber03. We conclude that although the nitrile absorption peak shape could be qualitatively predicted by the fixed charge Amber03 force field, the detailed electrostatic environment measured by the nitrile probe in terms of the extent of hydrogen bonding could only be accurately observed in the AMOEBA trajectories, where the permanent dipole, quadrupole, and dipole-induced-dipole polarizable interactions were all taken into account. The significance of this finding to the goal of accurately predicting electric fields in complex biomolecular environments is discussed.

Comparative Study of Molecular Mechanics Force Fields for β-Peptidic Foldamers: Folding and Self-Association.

Computer-assisted study and design of non-natural peptidomimetics is increasingly important in the development of novel constructs with widespread applicability. Among these methods, molecular dynamics can accurately describe monomeric as well as oligomeric states of these compounds. We studied seven different sequences composed of cyclic and acyclic β-amino acids, the closest homologues of natural peptides, and compared the performance on them of three force field families in which specific modifications were made to improve reproduction of β-peptide structures. Altogether 17 systems were simulated, each for 500 ns, testing multiple starting conformations and in three cases also oligomer formation and stability from eight β-peptide monomers. The results indicated that our recently developed CHARMM force field extension, based on torsional energy path matching of the β-peptide backbone against quantum-chemical calculations, performs best overall, reproducing the experimental structures accurately in all monomeric simulations and correctly describing all the oligomeric examples. The Amber and GROMOS force fields could only treat some of the seven peptides (four in each case) without further parametrization. Amber was able to reproduce the experimental secondary structure of those β-peptides which contained cyclic β-amino acids, while the GROMOS force field had the lowest performance in this sense. From the latter two, Amber was able to hold together already formed associates in the prepared state but was not able to yield spontaneous oligomer formation in the simulations.

Cysteine carbonylation with reactive carbonyl species from lipid peroxidation induce local structural changes on thioredoxin active site

Protein oxidative modifications with reactive carbonyl species (RCS) is directly linked to metabolic processes in premature aging, cancer, neurodegenerative and infectious diseases. RCS as 4-Hydroxy-2-nonal (HNE), 4-Hydroxy-2-hexenal (HHE), 4-Oxo-2-nonenal (ONE) and Malondialdehyde (MDA) attack nucleophilic amino acids residues forming irreversible adducts with proteins as Thioredoxins (Trx). This is a class of small thiol oxide-reductases playing a key role in redox signaling and oxidative stress responses in mammals. Although proteomic studies have identified to Cys-32 residue as a target of HNE attack that inhibit its enzymatic activity, how this carbonylation affects its structure and dynamic behavior at the atomic level is unknown. Even more, the molecular bases for the atomistic behavior of these modified proteins have not been completely understood. We present molecular dynamics simulations of Trx-modified with four different RCS to analyze its global and local structural effects. For this, parameters supported in the AMBER force fields were built and validated for three non-natural cysteine residues modified with HHE, ONE and MDA. Results obtained showed a slight change in the global conformational stability of Trx modified with HNE and MDA, establishing that all modified proteins presented local regions of high mobility in the modified catalytic site and some regions far from the modification area. In addition, essential domain movement modes evidences that proteins modified with the RCS assayed induce changes in conformational flexibility. Finally, these data showed that the given conformational changes did not caused global changes in proteins but rather localized changes in particular regions.

Surface Affinity of Tetramethylammonium Iodide in Aqueous Solutions: A Combined Experimental and Computer Simulation Study.

The surface affinity of tetramethylammonium iodide (TMAI) in aqueous solutions is investigated by surface tension measurements and molecular dynamics computer simulations. Experiments, performed in the entire composition range of solubility using the pendant drop method with two different setups, clearly reveal that TMAI is a weakly capillary active salt. Computer simulations performed with the AMBER force field reproduce the experimental data very well, while two other major force fields (i.e., CHARMM and OPLS) can still reproduce the experimental trend qualitatively; however, even qualitative reproduction of the experimental trend requires scaling down the ion charges according to the Leontyev-Stuchebrukhov correction. On the other hand, the GROMOS force field fails in reproducing the experimentally confirmed capillary activity of TMAI. Molecular dynamics simulation results show that, among the two ions, iodide has a clearly larger surface affinity than tetramethylammonium (TMA+). Further, the adsorption of the I- anions is strictly limited to the first molecular layer beneath the liquid-vapor interface, which is followed by several layers of their depletion. On the other hand, the net negative charge of the surface layer, caused by the excess amount of I- with respect to TMA+, is compensated by a diffuse layer of adsorbed TMA+ cations, extending to or beyond the fourth molecular layer beneath the liquid surface.

Computational-Simulation-Based Behavioral Analysis of Chemical Compounds

This research focuses on obtaining the behavior of chemical compounds with respect to their molecular weight and optimization energy based on the variation in properties in organic carbon links. Here, behavioral analysis of compounds is used in the application of a metal organic framework to denote the high-grade compounds. The grade was selected based on the essential measure of optimization energy and molecular weight, and in turn, depicts the stability of material. Computation of the optimization energy and molecular weight of chemical compounds was performed with Avogadro software. Several force fields can be considered to compute optimized energy. Exclusively, three force fields, namely, the Universal Force Field (UFF), the General Amber Force Field (GAFF), and the Ghemical force field (Ghemical) were selected from Avogadro as these were more relevant to compounds considered in this research. The various chemical compounds examined in this work are Aluminum (Al), Boron (Br), Calcium (Ca), Chlorine (Cl), Indium (In), Potassium (K), Scandium (Sc), Silicon (Si), and Tungsten (W). Hence, molecular modeling of different compounds incorporated with three different force fields was evaluated in this work. In this study, we found that the In structure has more energy reduction, of 22.673 kJ mol−1 in UFF, when compared with the other two force fields. Thus, In has higher potential with more stability.

Parameterization and validation of a new AMBER force field for an oxovanadium (IV) complex with therapeutic potential implications in Alzheimer's disease

The scarcity of efficient force fields to describe metal complexes may be a problem for new advances in medicinal chemistry. Thus, the development of force fields for these compounds can be valuable for the scientific community, especially when it comes to molecules that show interesting outputs regarding potential treating of diseases. Vanadium complexes, for instance, have shown promising results towards therapeutics of Alzheimer's Disease, most notably the bis(maltolato)oxovanadium (IV). Therefore, the mainly goal of this work is to develop and validate a new set of parameters for this vanadium complex from a minimum energy structure, obtained by DFT calculations, where great results of the new force field are found when confronted with experimental and quantum reference values. Moreover, the new force field showed to be quite effective to describe the molecule of under study whilst GAFF could not describe it effectively. In addition, a case study points out hydrogen bonds in the vanadium complex-PTP1B system.

Non-equilibrium virus particle dynamics: Microsecond MD simulations of the complete Flock House virus capsid under different conditions

Flock House virus (FHV) is an animal virus and considered a model system for non-enveloped viruses. It has a small, icosahedral capsid (T=3) and a bipartite positive-sense RNA genome. We present an extensive study of the FHV capsid dynamics from all-atom molecular dynamics simulations of the complete capsid. The simulations explore different biologically relevant conditions (neutral/low pH, with/without RNA in the capsid) using the CHARMM force field. The results show that low pH destabilizes the capsid, causing radial expansion, and RNA stabilizes the capsid. The finding of low pH destabilization is biologically relevant because the capsid is exposed to low pH in the endosome, where conformational changes occur leading to genome release. We also observe structural changes at the fivefold and twofold symmetry axes that likely relate to the externalization of membrane active γ peptides through the fivefold vertex and extrusion of RNA at the twofold axis. Simulations using the Amber force field at neutral pH are also performed and display similar characteristics to the CHARMM simulations.

Insight into the structural and transport properties of methyl and benzyl triphenyl phosphonium based deep eutectic solvents using molecular dynamics simulations

Molecular dynamics simulation of twelve phosphonium based DESs based on methyl triphenyl phosphonium bromide and benzyl triphenyl phosphonium chloride as hydrogen bond acceptors (HBA) with glycerol, ethylene glycol, triethylene glycol and trifluoroacetamide as hydrogen bond donors (HBDs) are carried out with the Generalized Amber Force Field between 25 °C and 95 °C at 1 atm pressure. Isobaric-isothermal ensemble is used for predicting the structural properties, namely, radial distribution function and coordination number. Further, time resolved trajectory data is correlated to predict the transport properties such as, self-diffusivity, binary-diffusivity, ionic conductivity and viscosity. The temperature dependence of predicted density is observed with 4.96 × 10−2 absolute average deviations from experimental dataset. Further, the self-diffusivities are predicted using Einstein's approach and ionic conductivity is calculated from Nernst-Einstein equation as well as Green-Kubo formulation. Further, the viscosity is also predicted using the Green-Kubo formulation. The predicted ionic conductivities and viscosities are fitted in the Vogel-Fulcher-Tammann (VFT) equation to calculate the VFT parameters for the respective DESs.

Morphology prediction for organic molecular crystals using various force fields in ADDICT

AbstractAll‐atom force fields are important for calculating interaction energies between growth units to predict crystal morphology. Our group at UCSB developed the ADDICT morphology design software to predict crystal morphology using mechanistic growth models driven by the generalized Amber force field (GAFF). In this study, the universal force field (UFF), the consistent force field (CFF), and the Coulomb‐London‐Pauli (CLP) force field are incorporated into ADDICT. We systematically test the lattice energies and crystal morphologies of olanzapine, adipic acid, rubrene, biphenyl, and naphthalene using all these force fields. The unit cells for these crystals are represented by the original CSD experimental structure, as well as optimized structures. Considering the high accuracy of CLP, its wide range of applications, and the fact that ADDICT can automatically specify the atomic charge and type required for this force field, we find that CLP is the best all‐atom model to drive morphology calculations.

A General Picture of Cucurbit[8]uril Host–Guest Binding: Recalibrating Bonded Interactions

Atomic-level understanding of the dynamic feature of host-guest interactions remains a central challenge in supramolecular chemistry. The remarkable guest binding behavior of the Cucurbiturils family of supramolecular containers makes them promising drug carriers. Among Cucurbit[n]urils, Cucurbit[8]uril (CB8) has an intermediate portal size and cavity volume. It can exploit almost all host-guest recognition motifs formed by this host family. In our previous work, an extensive computational investigation of the binding of seven commonly abused and structurally diverse drugs to the CB8 host was performed, and a general dynamic binding picture of CB8-guest interactions was obtained. Further, two widely used fixed-charge models for drug-like molecules were investigated and compared in great detail, aiming at providing guidelines in choosing an appropriate charge scheme in host-guest modelling. Iterative refitting of atomic charges leads to improved binding thermodynamics and the best root-mean-squared deviation from the experimental reference is 2.6 kcal/mol. In this work, we focus on a thorough evaluation of the remaining parts of classical force fields, i.e., the bonded interactions. The widely used general Amber force fields are assessed and refitted with generalized force-matching to improve the intra-molecular conformational preference, and thus the description of inter-molecular host-guest interactions. The interaction pattern and binding thermodynamics show a significant dependence on the modelling parameters. The refitted system-specific parameter set improves the consistency of the modelling results and the experimental reference significantly. Finally, combining the previous charge-scheme comparison and the current force-field refitting, we provide general guidelines for the theoretical modelling of host-guest binding.