A Cloud Computing Platform for Scalable Relative and Absolute Binding Free Energy Predictions: New Opportunities and Challenges for Drug Discovery.

Free energy perturbation (FEP) has become widely used in drug discovery programs for binding affinity prediction between candidate compounds and their biological targets. However, limitations of FEP applications also exist, including, but not limited to, high cost, long waiting time, limited scalability, and breadth of application scenarios. To overcome these problems, we have developed XFEP, a scalable cloud computing platform for both relative and absolute free energy predictions using optimized simulation protocols. XFEP enables large-scale FEP calculations in a more efficient, scalable, and affordable way, for example, the evaluation of 5000 compounds can be performed in 1 week using 50-100 GPUs with a computing cost roughly equivalent to the cost for the synthesis of only one new compound. By combining these capabilities with artificial intelligence techniques for goal-directed molecule generation and evaluation, new opportunities can be explored for FEP applications in the drug discovery stages of hit identification, hit-to-lead, and lead optimization based not only on structure exploitation within the given chemical series but also including evaluation and comparison of completely unrelated molecules during structure exploration in a larger chemical space. XFEP provides the basis for scalable FEP applications to become more widely used in drug discovery projects and to speed up the drug discovery process from hit identification to preclinical candidate compound nomination.

Quantifying the Fast Dynamics of HClO in Living Cells by a Fluorescence Probe Capable of Responding to Oxidation and Reduction Events within the Time Scale of Milliseconds.

The biological roles of reactive oxygen species (ROS) depend highly on their dynamics. However, it has been challenging for measuring the dynamics of ROS in cells. In this study, we address a core challenge in developing fluorescence probes for monitoring ROS dynamics by designing a redox couple that can respond rapidly to both oxidation and reduction events. We show that such molecules can be designed by taking advantage of the steric effects of electron-donating groups at the ortho position relative to the selenium center. We demonstrate this design in a new fluorescence probe named Fl-Se. Results reveal that Fl-Se and its oxidized product Fl-SeO rapidly respond to HClO, an important member of the ROS family, and glutathione (GSH), with t1/2 = 2.7 ms at [HClO] = 1 µM; t1/2 = 61 ms at [GSH] = 1 mM. When applied in cells, Fl-Se satisfactorily tracks the dynamics of intracellular HClO in H2O2-stimulated HL-60 cells, as well as the different dynamic behaviors of HClO fluctuations involved in the phorbol 12-myristate-13-acetate-activated immune response of RAW264.7 cells and the 3-deazaneplanocin A-induced apoptosis of HL 60 cells.

Electronic structure and microscopic charge-transport properties of a new-type diketopyrrolopyrrole-based material.

Recently, diketopyrrolopyrrole (DPP)-based materials have attracted much interest due to their promising performance as a subunit in organic field effect transistors. Using density functional theory and charge-transport models, we investigated the electronic structure and microscopic charge transport properties of the cyanated bithiophene-functionalized DPP molecule (compound 1). First, we analyzed in detail the partition of the total relaxation (polaron) energy into the contributions from each vibrational mode and the influence of bond-parameter variations on the local electron-vibration coupling of compound 1, which well explains the effects of different functional groups on internal reorganization energy (λ). Then, we investigated the structural and electronic properties of compound 1 in its isolated molecular state and in the solid state form, and further simulated the angular resolution anisotropic mobility for both electron- and hole-transport using two different simulation methods: (i) the mobility orientation function proposed in our previous studies (method 1); and (ii) the master equation approach (method 2). The calculated electron-transfer mobility (0.00003-0.784 cm(2) V(-1) s(-1) from method 1 and 0.02-2.26 cm(2) V(-1) s(-1) from method 2) matched reasonably with the experimentally reported value (0.07-0.55 cm(2) V(-1) s(-1) ). To the best of our knowledge, this is the first time that the transport parameters of compound 1 were calculated in the context of band model and hopping models, and both calculation results suggest that the intrinsic hole mobility is higher than the corresponding intrinsic electron mobility. Our calculation results here will be instructive to further explore the potential of other higher DPP-containing quinoidal small molecules.

Accurate and robust molecular crystal modeling using fragment-based electronic structure methods.

Accurately modeling molecular crystal polymorphism requires careful treatment of diverse intra- and intermolecular interactions which can be difficult to achieve without the use of high-level ab initio electronic structure techniques. Fragment-based methods like the hybrid many-body interaction QM/MM technique enable the application of accurate electronic structure models to chemically interesting molecular crystals. The theoretical underpinnings of this approach and the practical requirements for the QM and MM contributions are discussed. Benchmark results and representative applications to aspirin and oxalyl dihydrazide crystals are presented.

Development and Comprehensive Benchmark of a High-Quality AMBER-Consistent Small Molecule Force Field with Broad Chemical Space Coverage for Molecular Modeling and Free Energy Calculation.

Biomolecular simulations have become an essential tool in contemporary drug discovery, and molecular mechanics force fields (FFs) constitute its cornerstone. Developing a high quality and broad coverage general FF is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing FFs originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule FF with extensive chemical space coverage, and we provide Open Access parameters for the entire modeling community. To validate our FF, we carried out benchmarks of quantum mechanics (QM)/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our FF achieves a higher level of performance at reproducing QM energies and geometries than two popular open-source FFs, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein-ligand data sets, comprising 1079 pairs of ligands, the new FF achieves an overall root-mean-square error of 1.19 kcal/mol for ΔΔG and 0.92 kcal/mol for ΔG on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with those of the leading commercial series of OPLS FFs.

First-principles investigation of anisotropic electron and hole mobility in heterocyclic oligomer crystals.

Based on quantum chemistry calculations combined with the Marcus-Hush electron transfer theory, we investigated the charge-transport properties of oligothiophenes (nTs) and oligopyrroles (nPs) (n=6, 7, 8) as potential p- or n-type organic semiconductor materials. The results of our calculations indicate that 1) the nPs show intrinsic hole mobilities as high as or even higher than those of nTs, and 2) the vertical ionization potentials (VIPs) of the nPs are about 0.6-0.7 eV smaller than the corresponding VIPs of the nTs. Based on their charge-transport ability and hole-injection efficiency, the nPs have potential as p-type organic semiconducting materials. Furthermore, it was also found that the maximum values of the electron-transfer mobility for the nTs are larger by one-to-two orders of magnitude than the corresponding maximum values of hole-transfer mobility, which suggests that the nTs have the potential to be developed as promising n-type organic semiconducting materials owing to their electron mobility.

Communication: Constructing an implicit quantum mechanical/molecular mechanics solvent model by coarse-graining explicit solvent.

To avoid repeated, computationally expensive QM solute calculations while sampling MM solvent in QM/MM simulations, a new approach for constructing an implicit solvent model by coarse-graining the solvent properties over many explicit solvent configurations is proposed. The solvent is modeled using a polarizable force field that is parameterized in terms of distributed multipoles (electrostatics), polarizabilities (induction), and frequency-dependent polarizabilities (dispersion). The coarse-graining procedure exploits the ability to translate these properties to the center of each coarse-graining cell and average them over many solvent configurations before interacting them with the solute. A single coarse-grained QM/MM calculation of the interaction between a formamide solute and aqueous solvent reproduces the much more expensive average over many explicit QM/MM calculations with kJ/mol accuracy.

Practical quantum mechanics-based fragment methods for predicting molecular crystal properties.

Significant advances in fragment-based electronic structure methods have created a real alternative to force-field and density functional techniques in condensed-phase problems such as molecular crystals. This perspective article highlights some of the important challenges in modeling molecular crystals and discusses techniques for addressing them. First, we survey recent developments in fragment-based methods for molecular crystals. Second, we use examples from our own recent research on a fragment-based QM/MM method, the hybrid many-body interaction (HMBI) model, to analyze the physical requirements for a practical and effective molecular crystal model chemistry. We demonstrate that it is possible to predict molecular crystal lattice energies to within a couple kJ mol(-1) and lattice parameters to within a few percent in small-molecule crystals. Fragment methods provide a systematically improvable approach to making predictions in the condensed phase, which is critical to making robust predictions regarding the subtle energy differences found in molecular crystals.

Density functional theory study on electron and hole transport properties of organic pentacene derivatives with electron-withdrawing substituent.

Attaching electron-withdrawing substituent to organic conjugated molecules is considered as an effective method to produce n-type and ambipolar transport materials. In this work, we use density functional theory calculations to investigate the electron and hole transport properties of pentacene (PENT) derivatives after substituent and simulate the angular resolution anisotropic mobility for both electron and hole transport. Our results show that adding electron-withdrawing substituents can lower the energy level of lowest unoccupied molecular orbital (LUMO) and increase electron affinity, which are beneficial to the electron injection and ambient stability of the material. Also the LUMO electronic couplings for electron transport in these pentacene derivatives can achieve up to a hundred meV which promises good electron transport mobility, although adding electron-withdrawing groups will introduce the increase of electron transfer reorganization energy. The final results of our angular resolution anisotropic mobility simulations show that the electron mobility of these pentacene derivatives can get to several cm(2) V(-1) s(-1), but it is important to control the orientation of the organic material relative to the device channel to obtain the highest electron mobility. Our investigation provide detailed information to assist in the design of n-type and ambipolar organic electronic materials with high mobility performance.

Revealing quantitative structure-activity relationships of transport properties in acene and acene derivative organic materials.

The intermolecular electronic coupling (transfer integral) and the intramolecular vibronic coupling (reorganization energy) are key parameters determining the transport properties of organic electronic materials. Using quantum mechanism calculations, we revealed the correlation between the reorganization energies and the partial charge difference values on the conjugated acene backbone, which can be used to evaluate the reorganization energies for acene and acene derivative systems with the same conjugated backbone but different substitutional groups. We used rigorous quantitative functions to investigate the electronic coupling oscillation behavior in slipped-cofacial stacking acene and acene derivative molecules, and revealed characteristic parameters in the electronic coupling oscillation. We suggest using a similar strategy to establish the quantitative structure-activity relationship database for different families of organic semiconducting materials.

Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods.

Molecular crystal structure prediction is increasingly being applied to study the solid form landscapes of larger, more flexible pharmaceutical molecules. Despite many successes in crystal structure prediction, van der Waals-inclusive density functional theory (DFT) methods exhibit serious failures predicting the polymorph stabilities for a number of systems exhibiting conformational polymorphism, where changes in intramolecular conformation lead to different intermolecular crystal packings. Here, the stabilities of the conformational polymorphs of o-acetamidobenzamide, ROY, and oxalyl dihydrazide are examined in detail. DFT functionals that have previously been very successful in crystal structure prediction perform poorly in all three systems, due primarily to the poor intramolecular conformational energies, but also due to the intermolecular description in oxalyl dihydrazide. In all three cases, a fragment-based dispersion-corrected second-order Møller-Plesset perturbation theory (MP2D) treatment of the crystals overcomes these difficulties and predicts conformational polymorph stabilities in good agreement with experiment. These results highlight the need for methods which go beyond current-generation DFT functionals to make crystal polymorph stability predictions truly reliable.

A fluorophore's electron-deficiency does matter in designing high-performance near-infrared fluorescent probes.

The applications of most fluorescent probes available for Glutathione S-Transferases (GSTs), including NI3 which we developed recently based on 1,8-naphthalimide (NI), are limited by their short emission wavelengths due to insufficient penetration. To realize imaging at a deeper depth, near-infrared (NIR) fluorescent probes are required. Here we report for the first time the designing of NIR fluorescent probes for GSTs by employing the NIR fluorophore HCy which possesses a higher brightness, hydrophilicity and electron-deficiency relative to NI. Intriguingly, with the same receptor unit, the HCy-based probe is always more reactive towards glutathione than the NI-based one, regardless of the specific chemical structure of the receptor unit. This was proved to result from the higher electron-deficiency of HCy instead of its higher hydrophilicity based on a comprehensive analysis. Further, with caging of the autofluorescence being crucial and more difficult to achieve via photoinduced electron transfer (PET) for a NIR probe, the quenching mechanism of HCy-based probes was proved to be PET for the first time with femtosecond transient absorption and theoretical calculations. Thus, HCy2 and HCy9, which employ receptor units less reactive than the one adopted in NI3, turned out to be the most appropriate NIR probes with high-sensitivity and little nonenzymatic background noise. They were then successfully applied to detecting GST in cells, tissues and tumor xenografts in vivo. Additionally, unlike HCy2 with a broad isoenzyme selectivity, HCy9 is specific for GSTA1-1, which is attributed to its lower reactivity and the higher effectiveness of GSTA1-1 in stabilizing the active intermediate via H-bonds based on docking simulations.

First-principles investigation of anistropic hole mobilities in organic semiconductors.

We report a simple first-principles-based simulation model (combining quantum mechanics with Marcus-Hush theory) that provides the quantitative structural relationships between angular resolution anisotropic hole mobility and molecular structures and packing. We validate that this model correctly predicts the anisotropic hole mobilities of ruberene, pentacene, tetracene, 5,11-dichlorotetracene (DCT), and hexathiapentacene (HTP), leading to results in good agreement with experiment.

Improved organic hydrogen carriers with superior thermodynamic properties.

By the incorporation of N atoms into naphthalene, we present a theoretical investigation to seek for improved organic hydrogen carriers with an explicit guideline, the release of H2 is found to be greatly favored thermodynamically and the corresponding cycloalkanes possess high hydrogen storage capacity, this offers extensive candidates for practical applications of the promising hydrogen energy.

Quantitative prediction of charge mobilities of π-stacked systems by first-principles simulation.

This protocol is intended to provide chemists and physicists with a tool for predicting the charge carrier mobilities of π-stacked systems such as organic semiconductors and the DNA double helix. An experimentally determined crystal structure is required as a starting point. The simulation involves the following operations: (i) searching the crystal structure; (ii) selecting molecular monomers and dimers from the crystal structure; (iii) using density function theory (DFT) calculations to determine electronic coupling for dimers; (iv) using DFT calculations to determine self-reorganization energy of monomers; and (v) using a numerical calculation to determine the charge carrier mobility. For a single crystal structure consisting of medium-sized molecules, this protocol can be completed in ∼4 h. We have selected two case studies (a rubrene crystal and a DNA segment) as examples of how this procedure can be used.

Crystal Polymorphism in Oxalyl Dihydrazide: Is Empirical DFT-D Accurate Enough?

Crystalline oxalyl dihydrazide has five experimentally known polymorphs whose energetics are governed by subtle balances between intra- and intermolecular interactions, providing a severe challenge for theoretical crystal structure modeling. Previous work has shown that many common density functional methods that neglect van der Waals dispersion cannot correctly describe this system, but it has been argued that empirically dispersion-corrected DFT-D performs much better. Here, we examine these crystals with second-order Møller-Plesset perturbation theory (MP2) and related levels of theory using the fragment-based hybrid many-body interaction method. The energetics prove sensitive to the treatment of electron-electron correlation, the basis set, many-body induction, three-body dispersion, and zero-point contributions. Nevertheless, our best predictions for the polymorph energy ordering based on dispersion-corrected MP2C calculations agree with the available experimental data. In contrast, lower levels of theory, including the common B3LYP-D* and D-PW91 dispersion-corrected density functional approximations, fail to reproduce experimental observations and/or the high-level calculations.

First-principles investigation of the electronic and conducting properties of oligothienoacenes and their derivatives.

Herein, we calculated reorganization energies, vertical ionization energies, electron affinities, and HOMO-LUMO gaps of fused thiophenes and their derivatives, and analyzed the influence of different substituents on their electronic properties. Furthermore, we simulated the angular resolution anisotropic mobility for both electron- and hole-transport, based on quantum-chemical calculations combined with the Marcus-Hush electron-transfer theory. We showed that: 1) styrene-group substitution can effectively elevate the HOMO energy level and lower the LUMO energy level, and therefore lower both the hole- and electron-injection barriers; and 2) chemical oxidation of the thiophene ring can significantly improve the semiconductor properties of the fused oligothiophenes through a decrease of the injection barrier and an increase in the charge-transfer mobility for electrons but without lowering their hole-transfer mobilities, which suggests that it may be a promising way to convert p-type semiconductors into ambipolar or n-type semiconductor materials.

Accurate Molecular Crystal Lattice Energies from a Fragment QM/MM Approach with On-the-Fly Ab Initio Force Field Parametrization.

We combine quantum and classical mechanics in a fragment-based many-body interaction model to predict organic molecular crystal lattice energies. Individual molecules in the central unit cell and their short-range pairwise interactions are modeled quantum mechanically, while long-range pairwise and many-body interactions are approximated classically. The classical contributions are evaluated using an accurate ab initio force field that is constructed on-the-fly from quantum mechanical calculations on the individual molecules in the unit cell. The force field parameters include ab initio distributed multipole moments, distributed polarizabilities, and isotropic two- and three-body atomic dispersion coefficients. This QM/MM fragment model reproduces full periodic MP2 lattice energies to within a couple kJ/mol at substantially reduced cost. When high-level electronic structure methods are coupled with the ab initio force field, molecular crystal lattice energies are predicted to within 2 kJ/mol of their experimental values for six of the seven crystals examined here. Finally, Axilrod-Teller-Muto three-body dispersion energy plays a nontrivial role in several of the molecular crystals studied here.