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Non-equilibrium work switching simulations and Jarzynski's equation are a reliable method for computing free energy differences, Δ A low → high , between two levels of theory, such as a pure molecular mechanical (MM) and a quantum mechanical/molecular mechanical (QM/MM) description of a system of interest. Despite the inherent parallelism, the computational cost of this approach can quickly become very high. This is particularly true for systems where the core region, the part of the system to be described at different levels of theory, is embedded in an environment such as explicit solvent water. We find that even for relatively simple solute–water systems, switching lengths of at least 5 ps are necessary to compute Δ A low → high reliably. In this study, we investigate two approaches towards an affordable protocol, with an emphasis on keeping the switching length well below 5 ps. Inserting a hybrid charge intermediate state with modified partial charges, which resembles the charge distribution of the desired high level, makes it possible to obtain reliable calculations with 2 ps switches. Attempts using step-wise linear switching paths, on the other hand, did not lead to improvement, i.e., a faster convergence for all systems. To understand these findings, we analyzed the solutes' properties as a function of the partial charges used and the number of water molecules in direct contact with the solute, and studied the time needed for water molecules to reorient themselves upon a change in the solute's charge distribution. [ABSTRACT FROM AUTHOR]

The geometries and relative stabilities of the singlet and triplet states of carbenes were investigated. It was found that the resonance stabilization of both singlet and triplet carbenes increases modestly with the size of the arene substituent.

Small hydrocarbon complexes (X @ cage) incorporating cage-centered endohedral atoms and ions (X = H(super +), H, He, Ne, Ar, Li(super 0,+), Be(super 0,+,2+), Na(super 0,+), Mg(super 0,+,2+) are studied at the B3LYP/6-31G(d) hybrid HF/DFT level of theory. The study shows endohedral cage complexes with low parent cage strain energies, large cage internal cavity volumes, and a small, highly charged guest species are the most viable synthetic targets.

The relative energies obtained when density functional theory (DFT) was applied to cumulene and poly-yne isomers. It was clear from the results that as the carbon-chain length of cumulenes and poly-ynes increases the probability that bending modes are energetically accessible increases.

The three lowest-lying electronic states of PH2, X~B1(super 2), A~ A1(super 2) and B~B2(super 2) are studied by means of ab initio electronic structure theory. The total energies, equilibrium structures and physical properties are investigated using ab initio self-consistent field (SCF), configuration interaction (CISD), complete active space and coupled cluster wave functions with a wide variety of basis sets.

Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g., due to metals, co‐factors, etc.), and difficulty in retaining explicit water molecules. Herein, we present a novel CHARMM‐based induced fit docking (CIFDock) workflow that can circumvent these limitations by employing all‐atom force fields coupled to enhanced sampling molecular dynamics procedures. Self‐guided Langevin dynamics simulations are used to effectively sample relevant ligand conformations, side chain orientations, crystal water positions, and active site residue motion. Protein flexibility is further enhanced by dynamic sampling of side chain orientations using an expandable rotamer library. Steps in the procedure consisting of fixing individual components (e.g., the ligand) while sampling the other components (e.g., the residues in the active site of the protein) allow for the complex to adapt to conformational changes. Ultimately, all components of the complex—the protein, ligand, and waters—are sampled simultaneously and unrestrained with SGLD to capture any induced fit effects. This modular flexible docking procedure is automated using CHARMM scripting, interfaced with SLURM array processing, and parallelized to use the desired number of processors. We validated the CIFDock procedure by performing cross‐docking studies using a data set comprised of 21 pharmaceutically relevant proteins. Five variants of the CHARMM‐based SWISSDOCK scoring functions were created to quantify the results of the final generated poses. Results obtained were comparable to, or in some cases improved upon, commercial docking program data. [ABSTRACT FROM AUTHOR]

A new vibrational subsystem analysis (VSA) method is presented for coupling global motion to a local subsystem while including the inertial effects of the environment. The premise of the VSA method is a partitioning of a system into a smaller region of interest and a usually larger part referred to as environment. This method allows the investigation of local-global coupling, a more accurate estimation of vibrational free energy contribution for parts of a large system, and the elimination of the “tip effect” in elastic network model calculations. Additionally, the VSA method can be used as a probe of specific degrees of freedom that may contribute to free energy differences. The VSA approach can be employed in many ways, but it will likely be most useful for estimating activation free energies in QM/MM reaction path calculations. Four examples are presented to demonstrate the utility of this method. [ABSTRACT FROM AUTHOR]

Recently, it has been proposed that ab initio calculations cannot accurately treat molecules comprised of a benzene ring with a π-conjugated substituent, for example, benzaldehyde. Theoretical predictions of the benzaldehyde barrier to internal rotation are typically a factor of 2 too high in comparison to the experimental values of 4.67 (infared) and 4.90 (microwave) kcal mol-1. However, both experiments use Pitzer’s 1946 model to compute the reduced moment of inertia and employ the experimentally observed torsional frequency to deduce benzaldehyde’s rotational barrier. When Pitzer’s model is applied to a system with a nonconjugated functional group, such as phenol, the model and theoretical values are in close agreement. Therefore, we conclude the model may not account for conjugation between the substituent and the π-system of benzene. The experimental values of the benzaldehyde rotational barrier are therefore misleading. The true rotational barrier lies closer to the theoretically extrapolated limit of 7.7 kcal mol-1, based on coupled cluster theory. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The formation of different vacuum and solvent ab initio surfaces by the stereoelectronic and entropic stabilization of the exocyclic torsion of 5-(hydroxymethyl)tetrahydropyran is discussed. The solvent surface is shown to be more stable as compared to the vacuum and solvent surfaces.

The convergence of free energy perturbation (Zwanzig's equation) and its non-equilibrium extension (Jarzynski's equation) is herein investigated from a practical point of view. We focus on cases where neither intermediate steps nor two-sided methods (Bennett, Crooks) can be used to compute the free energy difference of interest. Using model data sampled from several probability densities, as well as comparing results of actual free energy simulations with reference values, we find, in agreement with existing theoretical work, that systematic errors are strongly correlated with the variance in the distribution of energy differences / non-equilibrium work values. The bias metric Π introduced by Wu and Kofke (J. Chem. Phys. 121, 8742 (2004)) is found to be a useful test for the presence of bias, i.e. systematic error in the results. By contrast, use of the second-order cumulant approximation to approximate the full Zwanzig or Jarzynski equation leads to poorer results in almost all cases. [ABSTRACT FROM PUBLISHER]

Background: A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings: Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions: The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. [ABSTRACT FROM AUTHOR]

Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (). This new module implements some of the most recent advances in modern machine learning algorithms-Random Forest, Support Vector Machine, Stochastic Gradient Descent, Gradient Tree Boosting, so forth. A user can import training data from Pubchem Bioassay data collections directly from our interface or upload his or her own SD files which contain structures and activity information to create new models (either categorical or numerical). A user can then track the model generation process and run models on new data to predict activity. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A module for fast determination of reduction potentials, E°, of redox-active proteins has been implemented in the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org). The free energy of reduction, which is proportional to E°, is composed of an intrinsic contribution due to the redox site and an environmental contribution due to the protein and solvent. Here, the intrinsic contribution is selected from a library of pre-calculated density functional theory values for each type of redox site and redox couple, while the environmental contribution is calculated from a crystal structure of the protein using Poisson-Boltzmann continuum electrostatics. An accompanying lesson demonstrates a calculation of E°. In this lesson, an ionizable residue in a [4Fe-4S]-protein that causes a pH-dependent E° is identified, and the E° of a mutant that would test the identification is predicted. This demonstration is valuable to both computational chemistry students and researchers interested in predicting sequence determinants of E° for mutagenesis. [ABSTRACT FROM AUTHOR]

Small hydrocarbon complexes (X@cage) incorporating cage-centered endohedral atoms and ions (X = H[sup +], H, He, Ne, Ar, Li[sup 0,+], Be[sup 0,+,2+], Na[sup 0,+], Mg[sup 0,+,2+]) have been studied at the B3LYP/6-31G(d) hybrid HF/DFT level of theory. No tetrahedrane (C[sub 4]H[sub 4], T[sub d]) endohedral complexes are minima, not even with the very small hydrogen atom or beryllium dication. Cubane (C[sub 8]H[sub 8], O[sub h]) and bicyclo[2.2.2]octane (C[sub 8]H[sub 14], D[sub 3h]) minima are limited to encapsulating species smaller than Ne and Na[sup +]. Despite its intermediate size, adamantane (C[sub 10]H[sub 16], T[sub d]) can enclose a wide variety of endohedral atoms and ions including H, He, Ne, Li[sup 0,+], Be[sup 0,+,2+], Na[sup 0,+], and Mg[sup 2+]. In contrast, the truncated tetrahedrane (C[sub 12]H[sub 12], T[sub d]) encapsulates fewer species, while the D[sub 4d] symmetric C[sub 16]H[sub 16] hydrocarbon cage (see Table of Contents graphic) encapsulates all but the larger Be, Mg, and Mg[sup +] species. The host cages have more compact geometries when metal atoms, rather than cations, are inside. This is due to electron donation from the endohedral metals into C-C bonding and C-H antibonding cage molecular orbitals. The relative stabilities of endohedral minima are evaluated by comparing their energies (E[sub endo]) to the sum of their isolated components (E[sub inc] = E[sub endo] - E[sub cage] - E[sub x]) and to their exohedral isomer energies (E[sub isom] = E[sub endo] - E[sub exo]). Although exohedral binding is preferred to endohedral encapsulation without exception (i.e., E[sub isom] is always exothermic), Be[sup 2+] @C[sub 10]H[sub 16] (T[sub d]; -235.5 kcal/mol), Li[sup +] @C[sub 12]H[sub 12] (T[sub d]; 50.2 kcal/mol), Be[sup 2+]@C[sub 12]H[sub 12] (T[sub d]; -181.2 kcal/mol), Mg[sup 2+]@C[sub 12]H[sub 12] (T[sub d]; -45.0 kcal/mol), Li[sup +]@C[sub 16]H[sub 16] (D[sub 4d]; 13.3 kcal/mol), Be[sup +]@C[sub 16]H[sub 16] (C[sub 4v]; 31.8 kcal/mol), Be[sup 2+]@C[sub 16]H[sub 16] (D[sub 4d]; -239.2 kcal/mol), and Mg[sup 2+]-C[sub 16]H[sub 16] (D[sub 4d]; -37.7 kcal/mol) are relatively stable as compared to experimentally known He@C[sub 20]H[sub 20] (l[sub h]), which has an E[sub inc] = 37.9 kcal/mol and E[sub isorn] = -35.4 kcal/mol. Overall, endohedral cage complexes with low parent cage strain energies, large cage internal cavity volumes, and a small, highly charged guest species are the most viable synthetic targets. [ABSTRACT FROM AUTHOR]

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on chemical space, drug-likeness, predicted toxicity, and virtual screens. Previous drug-likeness measures: the rule-of-five, quantitative estimate of drug-likeness (QED), and relative drug likelihoods (RDL) are based on a relatively small number of molecular properties. We augmented this approach using reference drug and toxin data sets defined for 51 predicted molecular properties. Cnidaria natural products overlap with drugs and toxins in this chemical space, although a multivariate test suggests that there are some differences between the groups. In terms of the established drug-likeness measures, Cnidaria natural products have generally lower QED and RDL scores than drugs, with a higher prevalence of metabolites that exceed at least one rule-of-five threshold. An index of drug-likeness that includes predicted toxicity (ADMET-score), however, found that Cnidaria natural products were more favourable than drugs. A measure of the distance of individual Cnidaria natural products to the centre of the drug distribution in multivariate chemical space was related to RDL, ADMET-score, and the number of rule-of-five exceptions. This multivariate similarity measure was negatively correlated with the QED score for the same metabolite, suggesting that the different approaches capture different aspects of the drug-likeness of individual metabolites. The contrasting of different drug similarity measures can help summarise the range of drug potential in the Cnidaria natural product data set. The most favourable metabolites were around 210–265 Da, quite often sesquiterpenes, with a moderate degree of complexity. Virtual screening against cancer-relevant targets found wide evidence of affinities, with Glide scores <−7 in 19% of the Cnidaria natural products. [ABSTRACT FROM AUTHOR]

The quantum chemistry community has developed analytic forces for approximate electronic excited states to enable walking on excited state potential energy surfaces (PES). One can thereby computationally characterize excited state minima and saddle points. Always implicit in using this machinery is the fact that an excited state PES only exists within the realm of the Born-Oppenheimer approximation, where the nuclear and electronic degrees of freedom separate. This work demonstrates through ab initio calculations and simple nonadiabatic dynamics that some excited state minimum structures are fantastical: they appear to exist as stable configurations only as a consequence of the PES construct, rather than being physically observable. Each fantastical structure exhibits an unphysically high predicted harmonic frequency and associated force constant. This fact can serve as a valuable diagnostic of when an optimized excited state structure is non-observable. The origin of this phenomenon can be attributed to the coupling between different electronic states. As PESs approach one another, the upper surface can form a minimum that is very close to a near-touching point. The force constant, evaluated at this minimum, relates to the strength of the electronic coupling rather than to any characteristic excited state vibration. Nonadiabatic dynamics results using a Landau-Zener model illustrate that fantastical excited state structures have extremely short lifetimes on the order of a few femtoseconds. Their appearance in a calculation signals the presence of a nearby conical intersection through which the system will rapidly cross to a lower surface. [ABSTRACT FROM AUTHOR]

In this study, we investigate the influence of chiral and achiral cations on the enantiomerization of biphenylic anions in n-butylmethylether and water. In addition to the impact of the cations and solvent molecules on the free energy profile of rotation, we also explore if chirality transfer between a chiral cation and the biphenylic anion is possible, i.e., if pairing with a chiral cation can energetically favour one conformer of the anion via diastereomeric complex formation. The quantum-mechanical calculations are accompanied by polarizable MD simulations using umbrella sampling to study the impact of solvents of different polarity in more detail. We also discuss how accurate polarizable force fields for biphenylic anions can be constructed from quantum-mechanical reference data. [ABSTRACT FROM AUTHOR]