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Despite the massive application of end-point free energy methods in protein–ligand and protein–protein interactions, computational understandings about their performance in relatively simple and prototypical host–guest systems are limited. In this work, we present a comprehensive benchmark calculation with standard end-point free energy techniques in a recent host–guest dataset containing 13 host–guest pairs involving the carboxylated-pillar[6]arene host. We first assess the charge schemes for solutes by comparing the charge-produced electrostatics with many ab initio references, in order to obtain a preliminary albeit detailed view of the charge quality. Then, we focus on four modelling details of end-point free energy calculations, including the docking procedure for the generation of initial condition, the charge scheme for host and guest molecules, the water model used in explicit-solvent sampling, and the end-point methods for free energy estimation. The binding thermodynamics obtained with different modelling schemes are compared with experimental references, and some practical guidelines on maximizing the performance of end-point methods in practical host–guest systems are summarized. Further, we compare our simulation outcome with predictions in the grand challenge and discuss further developments to improve the prediction quality of end-point free energy methods. Overall, unlike the widely acknowledged applicability in protein–ligand binding, the standard end-point calculations cannot produce useful outcomes in host–guest binding and thus are not recommended unless alterations are performed. [ABSTRACT FROM AUTHOR]

The absolute binding free energies and binding enthalpies of twelve host-guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R2) of 0.8 and root-mean-squared error of 1.7 kcal/mol using the TIP3P water model. The binding enthalpy calculations achieve moderate correlations, with R2 of 0.5 and RMSE of 2.5 kcal/mol, for TIP3P water. Calculations using the newly developed OPC water model also show good performance. Furthermore, the present calculations semi-quantitatively capture the experimental trend of enthalpy-entropy compensation observed, and successfully predict guests with the strongest and weakest binding affinity. The most populated binding poses of all twelve systems, based on clustering analysis of 750 ns molecular dynamics (MD) trajectories, were extracted and analyzed. Computational methods using MD simulations and explicit solvent models in a rigorous statistical thermodynamic framework, like APR, can generate reasonable predictions of binding thermodynamics. Especially with continuing improvement in simulation force fields, such methods hold the promise of making substantial contributions to hit identification and lead optimization in the drug discovery process.

As part of the SAMPL7 host–guest binding challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for 16 charged organic ammonium guests to the TrimerTrip host, a recently reported acyclic cucurbituril-derived clip host structure with triptycene moieties at its termini. Here we report binding free energy calculations for this system using the AMOEBA polarizable atomic multipole force field and double annihilation free energy methodology. Conformational analysis of the host suggests three families of conformations that do not interconvert in solution on a time scale available to nanosecond molecular dynamics (MD) simulations. Two of these host conformers, referred to as the "indent" and "overlap" structures, are capable of binding guest molecules. As a result, the free energies of all 16 guests binding to both conformations were computed separately, and combined to produce values for comparison with experiment. Initial ranked results submitted as part of the SAMPL7 exercise had a mean unsigned error (MUE) from experimental binding data of 2.14 kcal/mol. Subsequently, a rigorous umbrella sampling reference calculation was used to better determine the free energy difference between unligated "indent" and "overlap" host conformations. Revised binding values for the 16 guests pegged to this umbrella sampling reference reduced the MUE to 1.41 kcal/mol, with a correlation coefficient (Pearson R) between calculated and experimental binding values of 0.832 and a rank correlation (Kendall τ) of 0.65. Overall, the AMOEBA results demonstrate no significant systematic error, suggesting the force field provides an accurate energetic description of the TrimerTrip host, and an appropriate balance of solvation and desolvation effects associated with guest binding. [ABSTRACT FROM AUTHOR]

In the current work we report on our participation in the SAMPL7 challenge calculating absolute free energies of the host–guest systems, where 2 guest molecules were probed against 9 hosts-cyclodextrin and its derivatives. Our submission was based on the non-equilibrium free energy calculation protocol utilizing an averaged consensus result from two force fields (GAFF and CGenFF). The submitted prediction achieved accuracy of 1.38 kcal / mol in terms of the unsigned error averaged over the whole dataset. Subsequently, we further report on the underlying reasons for discrepancies between our calculations and another submission to the SAMPL7 challenge which employed a similar methodology, but disparate ligand and water force fields. As a result we have uncovered a number of issues in the dihedral parameter definition of the GAFF 2 force field. In addition, we identified particular cases in the molecular topologies where different software packages had a different interpretation of the same force field. This latter observation might be of particular relevance for systematic comparisons of molecular simulation software packages. The aforementioned factors have an influence on the final free energy estimates and need to be considered when performing alchemical calculations. [ABSTRACT FROM AUTHOR]

As part of the SAMPL6 host-guest blind challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for a cucurbit[8]uril host complexed with 14 diverse guests, ranging from small, rigid structures to drug molecules. The AMOEBA results from the initial submission prompted an investigation into aspects of the methodology and parameterization employed. Lessons learned from the blind challenge include: a double annihilation scheme (electrostatics and van der Waals) is needed to obtain proper sampling of guest conformations, annihilation of key torsion parameters of the guest are recommended for flexible guests, and a more thorough analysis of torsion parameters is warranted. When put in to practice with the AMOEBA model, the lessons learned improved the MUE from 2.63 to 1.20 kcal/mol and the RMSE from 3.62 to 1.68 kcal/mol, respectively. Overall, the AMOEBA protocol for determining absolute binding free energies benefitted from participation in the SAMPL6 host-guest blind challenge and the results suggest the implementation of the methodology in future host-guest calculations. [ABSTRACT FROM AUTHOR]

Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three-dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO-AETAAAKFLRAHA-NH). For chignolin, REMC/SAAP3D simulation correctly produced native β-turn structures, whose minimal all-atom root-mean-square deviation value measured from the native NMR structure (except for H) was 1.2 Å, at 300 K in implicit water, along with misfolded β-hairpin structures with unpacked aromatic side chains of Tyr2 and Trp9. Similar results were obtained for chignolin analog [G1Y,G10Y], which folded more tightly to the native β-turn structure than chignolin did. For C-peptide, on the other hand, the α-helix content was larger than the β content on average, suggesting a significant helix-forming propensity. When the imidazole side chain of His12 was protonated (i.e., [His12Hip]), the α content became larger. These observations as well as the representative structures obtained by clustering analysis were in reasonable agreement not only with the structures of C-peptide that were determined in this study by NMR in 30% CDCD in HO at 298 K but also with the experimental and theoretical behaviors having been reported for protonated C-peptide. Thus, accuracy of the SAAP force field was improved by applying three-dimensional main-chain parameters, supporting prominent importance of SAAP for peptide conformations. [ABSTRACT FROM AUTHOR]

Alchemical transformation of solutes using classical fixed-charge force fields is a popular strategy for assessing the free energy of transfer in different environments. Accurate estimations of transfer between phases with significantly different polarities can be difficult because of the static nature of the force fields. Here, we report on an application of such calculations in the SAMPL5 experiment that also involves an effort in balancing solute and solvent interactions via their expected static dielectric constants. This strategy performs well with respect to predictive accuracy and correlation with unknown experimental values. We follow this by performing a series of retrospective investigations which highlight the potential importance of proper balancing in these systems, and we use a null hypothesis analysis to explore potential biases in the comparisons with experiment. The collective findings indicate that considerations of force field compatibility through dielectric behavior is a potential strategy for future improvements in transfer processes between disparate environments. [ABSTRACT FROM AUTHOR]

S-Adenosylmethionine (AdoMet) is involved in many biological processes as cofactor in enzymes transferring its sulfonium methyl group to various substrates. Additionally, it is used as drug and nutritional supplement to reduce the pain in osteoarthritis and against depression. Due to the biological relevance of AdoMet it has been part of various computational simulation studies and will also be in the future. However, to our knowledge no rigorous force field parameter development for its simulation in biological systems has been reported. Here, we use electronic structure calculations combined with molecular dynamics simulations in explicit solvent to develop force field parameters compatible with the AMBER99 force field. Additionally, we propose new dynamic Hirshfeld-I atomic charges which are derived from the polarized electron density of AdoMet in aqueous solution to describe its electrostatic interactions in biological systems. The validation of the force field parameters and the atomic charges is performed against experimental interproton NOE distances of AdoMet in aqueous solution and crystal structures of AdoMet in the cavity of three representative proteins. Graphical Abstract: A S-Adenosylmethionine force field was developed together with Dynamic Hirshfeld-I charges (shown color coded in figure) and validated against various experimental data. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Accurate methods for predicting protein-ligand binding affinities are of central interest to computer-aided drug design for hit identification and lead optimization. Here, we used the mining minima (M2) method to predict cucurbit[7]uril binding affinities from the SAMPL4 blind prediction challenge. We tested two different energy models, an empirical classical force field, CHARMm with VCharge charges, and the Poisson-Boltzmann surface area solvation model; and a semiempirical quantum mechanical (QM) Hamiltonian, PM6-DH+, coupled with the COSMO solvation model and a surface area term for nonpolar solvation free energy. Binding affinities based on the classical force field correlated strongly with the experiments with a correlation coefficient (R) of 0.74. On the other hand, binding affinities based on the QM energy model correlated poorly with experiments (R = 0.24), due largely to two major outliers. As we used extensive conformational search methods, these results point to possible inaccuracies in the PM6-DH+ energy model or the COSMO solvation model. Furthermore, the different binding free energy components, solute energy, solvation free energy, and configurational entropy showed significant deviations between the classical M2 and quantum M2 calculations. Comparison of different classical M2 free energy components to experiments show that the change in the total energy, i.e. the solute energy plus the solvation free energy, is the key driving force for binding, with a reasonable correlation to experiment (R = 0.56); however, accounting for configurational entropy further improves the correlation. [ABSTRACT FROM AUTHOR]

The Cambridge Structural Database (CSD) offers an excellent data source to study small molecule conformations and molecular interactions. We have analyzed 130 small molecules from the CSD containing an intramolecular sulfur-oxygen distance less than the sum of their van der Waals (vdW) radii. Close S···O distances are observed in several important medicinal chemistry motifs (e.g. a carbonyl oxygen connected by a carbon or nitrogen linker to a sulfur) and are not treated well with existing parameters in the MMFFs or OPLS_2005 force fields, resulting in suboptimal geometries and energetics. In this work, we develop modified parameters for the OPLS_2005 force field to better treat this specific interaction in order to generate conformations close to those found in the CSD structures. We use a combination of refitting a force field torsional parameter, adding a specific atom pair vdW term, and attenuating the electrostatic interactions to obtain an improvement in the accuracy of geometry minimizations and conformational searches for these molecules. Specifically, in a conformational search 58 % of the cases produced a conformation less than 0.25 Å from the CSD crystal conformation with the modified OPLS force field parameters developed in this work. In contrast, 25 and 37 % produced a conformation less than 0.25 Å with the MMFFs and OPLS_2005 force fields, respectively. As an application of the new parameters, we generated conformations for the tyrosine kinase inhibitor axitinib (trade name Inlyta) that could be correctly repacked into three observed polymorphic structures, which was not possible with conformations generated using MMFFs or OPLS_2005. The improved parameters can be mapped directly onto physical characteristics of the systems that are treated inadequately with the molecular mechanics force fields used in this study and potentially other force fields as well. [ABSTRACT FROM AUTHOR]

We report here a test of the Semi-Explicit Assembly (SEA) model in the solvation free energy category of the SAMPL3 blind prediction event (summer 2011). We tested how dependent the SEA results are on the chosen force field by performing calculations with both the General Amber and OPLS force fields. We compared our SEA results with full molecular dynamics simulations in explicit solvent. Of the 20 submissions, our SEA/OPLS results gave the second smallest RMS errors in free energies compared to experiments. SEA gives results that are very similar to those of its underlying force field and explicit solvent model. Hence, while the SEA water modeling approach is much faster than explicit solvent simulations, its predictions appear to be just as accurate. [ABSTRACT FROM AUTHOR]

Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated αL rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L-amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods. [ABSTRACT FROM AUTHOR]

The Surflex flexible molecular docking method has been generalized and extended in two primary areas related to the search component of docking. First, incorporation of a small-molecule force-field extends the search into Cartesian coordinates constrained by internal ligand energetics. Whereas previous versions searched only the alignment and acyclic torsional space of the ligand, the new approach supports dynamic ring flexibility and all-atom optimization of docked ligand poses. Second, knowledge of well established molecular interactions between ligand fragments and a target protein can be directly exploited to guide the search process. This offers advantages in some cases over the search strategy where ligand alignment is guided solely by a “protomol” (a pre-computed molecular representation of an idealized ligand). Results are presented on both docking accuracy and screening utility using multiple publicly available benchmark data sets that place Surflex’s performance in the context of other molecular docking methods. In terms of docking accuracy, Surflex-Dock 2.1 performs as well as the best available methods. In the area of screening utility, Surflex’s performance is extremely robust, and it is clearly superior to other methods within the set of cases for which comparative data are available, with roughly double the screening enrichment performance. [ABSTRACT FROM AUTHOR]

Aromatic amino acid residues are often present in carbohydrate-binding sites of proteins. These binding sites are characterized by a placement of a carbohydrate moiety in a stacking orientation to an aromatic ring. This arrangement is an example of CH/π interactions. Ab initio interaction energies for 20 carbohydrate–aromatic complexes taken from 6 selected ultra-high resolution X-ray structures of glycosidases and carbohydrate-binding proteins were calculated. All interaction energies of a pyranose moiety with a side chain of an aromatic residue were calculated as attractive with interaction energy ranging from −2.8 to −12.3 kcal/mol as calculated at the MP2/6-311+G(d) level. Strong attractive interactions were observed for a wide range of orientations of carbohydrate and aromatic ring as present in selected X-ray structures. The most attractive interaction was associated with apparent combination of CH/π interactions and classical H-bonds. The failure of Hartree–Fock method (interaction energies from +1.0 to −6.9 kcal/mol) can be explained by a dispersion nature of a majority of the studied complexes. We also present a comparison of interaction energies calculated at the MP2 level with those calculated using molecular mechanics force fields (OPLS, GROMOS, CSFF/CHARMM, CHEAT/CHARMM, Glycam/AMBER, MM2 and MM3). For a majority of force fields there was a strong correlation with MP2 values. RMSD between MP2 and force field values were 1.0 for CSFF/CHARMM, 1.2 for Glycam/AMBER, 1.2 for GROMOS, 1.3 for MM3, 1.4 for MM2, 1.5 for OPLS and to 2.3 for CHEAT/CHARMM (in kcal/mol). These results show that molecular mechanics approximates interaction energies very well and support an application of molecular mechanics methods in the area of glycochemistry and glycobiology. [ABSTRACT FROM AUTHOR]

Protein kinases are an important class of enzymes controlling virtually all cellular signaling pathways. Consequently, selective inhibitors of protein kinases have attracted significant interest as potential new drugs for many diseases. Computational methods, including molecular docking, have increasingly been used in the inhibitor design process [1]. We have considered several docking packages in order to strengthen our kinase inhibitor work with computational capabilities. In our experience, AutoDock offered a reasonable combination of accuracy and speed, as opposed to methods that specialize either in fast database searches or detailed and computationally intensive calculations. However, AutoDock did not perform well in cases where extensive hydrophobic contacts were involved, such as docking of SB203580 to its target protein kinase p38. Another shortcoming was a hydrogen bonding energy function, which underestimated the attraction component and, thus, did not allow for sufficiently accurate modeling of the key hydrogen bonds in the kinase-inhibitor complexes. We have modified the parameter set used to model hydrogen bonds, which increased the accuracy of AutoDock and appeared to be generally applicable to many kinase-inhibitor pairs without customization. Binding to largely hydrophobic sites, such as the active site of p38, was significantly improved by introducing a correction factor selectively affecting only carbon and hydrogen energy grids, thus, providing an effective, although approximate, treatment of solvation. [ABSTRACT FROM AUTHOR]

The complex structure of glucose oxidase (GOX) with the substrate glucose was determined using a docking algorithm and subsequent molecular dynamics simulations. Semiempirical quantum chemical calculations were used to investigate the role of the enzyme and FAD co-enzyme in the catalytic oxidation of glucose. On the basis of a small active site model, substrate binding residues were determined and heats of formation were computed for the enzyme substrate complex and different potential products of the reductive half reaction. The influence of the protein environment on the active site model was estimated with a point charge model using a mixed QM/MM method. Solvent effects were estimated with a continuum model. Possible modes of action are presented in relation to experimental data and discussed with respect to related enzymes. The calculations indicate that the redox reaction of GOX differs from the corresponding reaction of free flavins as a consequence of the protein environment. One of the active site histidines is involved in substrate binding and stabilization of potential intermediates, whereas the second histidine is a proton acceptor. The former one, being conserved in a series of oxidoreductases, is also involved in the stabilization of a C4a-hydroperoxy dihydroflavin in the course of the oxidative half reaction. [ABSTRACT FROM AUTHOR]

A simple and fast method to calculate charge distributions in organic molecules is presented. The method is based on charge shifts within the saturated σ-system, driven by orbital electronegativities, coupled to a modified Hückel treatment of the unsaturated π-systems. Experimental molecular dipole moments of a set of 119 molecules are reproduced with a root mean square deviation of 0.36 Debye units. Furthermore, the obtained charge distribution is used to describe hydration free energies in terms of hydrogen-bonding donor and acceptor strengths of polar groups. Least square fitting to experimental data of 281 compounds leads to values for these strengths with accuracy limits of ±4.3% and ±2.5%, respectively. Properly normalized values are taken to parametrize the hydrogen bonding terms in our MAB force field. The method is sufficiently fast to be used in the preparatory phase of interactive force-field calculations. [ABSTRACT FROM AUTHOR]

New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An additional fast search step is introduced between the initial perturbation and energy minimization. The fast search produces approximate low-energy structures, which are likely to minimize to a low energy. For template fitting, QXP uses a superposition force field which automatically assigns short-range attractive forces to similar atoms in different molecules. The docking algorithms were evaluated using X-ray data for 12 protein–ligand complexes. The ligands had up to 24 rotatable bonds and ranged from highly polar to mostly nonpolar. Docking searches of the randomly disordered ligands gave rms differences between the lowest energy docked structure and the energy-minimized X-ray structure, of less than 0.76 Å for 10 of the ligands. For all the ligands, the rms difference between the energy-minimized X-ray structure and the closest docked structure was less than 0.4 Å, when parts of one of the molecules which are in the solvent were excluded from the rms calculation. Template fitting was tested using four ACE inhibitors. Three ACE templates have been previously published. A single run using QXP generated a series of templates which contained examples of each of the three. A pseudo-receptor, complementary to an ACE template, was built out of small molecules, such as pyrrole, cyclopentanone and propane. When individually energy minimized in the pseudo-receptor, each of the four ACE inhibitors moved with an rms of less than 0.25 Å. After random perturbation, the inhibitors were docked into the pseudo-receptor. Each lowest energy docked structure matched the energy-minimized geometry with an rms of less than 0.08 Å. Thus, the pseudo-receptor shows steric and chemical complementarity to all four molecules. The QXP program is reliable, easy to use and sufficiently rapid for routine application in structure-based drug design. [ABSTRACT FROM AUTHOR]

Here we are making some predictions based on three methods: a straightforward extrapolations of the existing trends; a self-fulfilling prophecy; and picking some current grievances and predicting that they will be addressed or solved. We predict the growth of multicore computing and dramatic growth of data, as well as the improvements in force fields and sampling methods. We also predict that effects of therapeutic and environmental molecules on human body, as well as complex natural chemical signalling will be understood in terms of three dimensional models of their binding to specific pockets. [ABSTRACT FROM AUTHOR]