Enforcing Local DNA Kinks by Sequence-Selective Trisintercalating Oligopeptides of a Tricationic Porphyrin: A Polarizable Molecular Dynamics Study.

Bisacridinyl-bisarginyl porphyrin (BABAP) is a trisintercalating derivative of a tricationic porphyrin, formerly designed and synthesized in order to selectively target and photosensitize the ten-base pair palindromic sequence d(CGGGCGCCCG)2 . We resorted to the previously derived (Far et al., 2004) lowest energy-minimized (EM) structure of the BABAP complex with this sequence as a starting point. We performed polarizable molecular dynamics (MD) on this complex. It showed, over a 150 ns duration, the persistent binding of the Arg side-chain on each BABAP arm to the two G bases upstream from the central porphyrin intercalation site. We subsequently performed progressive shortenings of the connector chain linking the Arg-Gly backbone to the acridine, from n=6 methylenes to 4, followed by removal of the Gly backbone and further connector shortenings, from n=4 to n=1. These resulted into progressive deformations ('kinks') of the DNA backbone. In its most accented kinked structure, the DNA backbone was found to have a close overlap with that of DNA bound to Cre recombinase, with, at the level of one acridine intercalation site, negative roll and positive tilt values consistent with those experimentally found for this DNA at its own kinked dinucleotide sequence. Thus, in addition to their photosensitizing properties, some BABAP derivatives could induce sequence-selective, controlled DNA deformations, which are targets for cleavage by endonucleases or for repair enzymes.

Force Field X: A computational microscope to study genetic variation and organic crystals using theory and experiment.

Force Field X (FFX) is an open-source software package for atomic resolution modeling of genetic variants and organic crystals that leverages advanced potential energy functions and experimental data. FFX currently consists of nine modular packages with novel algorithms that include global optimization via a many-body expansion, acid-base chemistry using polarizable constant-pH molecular dynamics, estimation of free energy differences, generalized Kirkwood implicit solvent models, and many more. Applications of FFX focus on the use and development of a crystal structure prediction pipeline, biomolecular structure refinement against experimental datasets, and estimation of the thermodynamic effects of genetic variants on both proteins and nucleic acids. The use of Parallel Java and OpenMM combines to offer shared memory, message passing, and graphics processing unit parallelization for high performance simulations. Overall, the FFX platform serves as a computational microscope to study systems ranging from organic crystals to solvated biomolecular systems.

Extension of the Trotterized Unitary Coupled Cluster to Triple Excitations.

The Trotterized Unitary Coupled Cluster Single and Double (UCCSD) ansatz has recently attracted interest due to its use in Variation Quantum Eigensolver (VQE) molecular simulations on quantum computers. However, when the size of molecules increases, UCCSD becomes less interesting as it cannot achieve sufficient accuracy. Including higher-order excitations is therefore mandatory to recover the UCC's missing correlation effects. Here, we extend the Trotterized UCC approach via the addition of (true) Triple T excitations introducing UCCSDT. We also include both spin and orbital symmetries. Indeed, in practice, the latter help to reduce unnecessary circuit excitations and thus accelerate the optimization process enabling researchers to tackle larger molecules. Our initial numerical tests (12-14 qubits) show that UCCSDT improves the overall accuracy by at least two orders of magnitude with respect to standard UCCSD. Overall, the UCCSDT ansatz is shown to reach chemical accuracy and to be competitive with the CCSD(T) gold-standard classical method of quantum chemistry.

Smooth particle mesh Ewald-integrated stochastic Lanczos many-body dispersion algorithm.

We derive and implement an alternative formulation of the Stochastic Lanczos algorithm to be employed in connection with the Many-Body Dispersion model (MBD). Indeed, this formulation, which is only possible due to the Stochastic Lanczos' reliance on matrix-vector products, introduces generalized dipoles and fields. These key quantities allow for a state-of-the-art treatment of periodic boundary conditions via the O(Nlog(N)) Smooth Particle Mesh Ewald (SPME) approach which uses efficient fast Fourier transforms. This SPME-Lanczos algorithm drastically outperforms the standard replica method which is affected by a slow and conditionally convergence rate that limits an efficient and reliable inclusion of long-range periodic boundary conditions interactions in many-body dispersion modelling. The proposed algorithm inherits the embarrassingly parallelism of the original Stochastic Lanczos scheme, thus opening up for a fully converged and efficient periodic boundary conditions treatment of MBD approaches.

Atomistic Polarizable Embeddings: Energy, Dynamics, Spectroscopy, and Reactivity.

The computational modeling of realistic extended systems, relevant in, e.g., Chemistry and Biophysics, is a fundamental problem of paramount importance in contemporary research. Enzymatic catalysis and photoinduced processes in pigment-protein complexes are typical problems targeted by computer-aided approaches, to complement experiments as interpretative tools at a molecular scale. The daunting complexity of this task lies in between the opposite stringent requirements of results' reliability for structural/dynamical properties and related intermolecular interactions, and a mandatory principle of realism in the modeling strategy. Therefore, in practice, a truly realistic computational model of a biologically relevant system can easily fail to meet the accuracy requirement, in order to balance the excessive computational cost necessary to reach the desired precision.To address such an "accuracy vs reality" dualistic requirement, mixed quantum mechanics/classical mechanics approaches within Atomistic (i.e., preserving the discrete particle configuration) Polarizable Embeddings (QM/APEs) methods have been proposed over the years. In this Account, we review recent developments in the design and application of general QM/APE methods, targeting situations where a local intrinsically quantum behavior is coupled to a large molecular system (i.e., an environment), often involving processes with different dynamical time scales, in order to avoid brute-force, unpractical quantum chemistry calculations on the complete system.In the first place, our interest is devoted to the available APEs models presently implemented in computational software, highlighting the quantum chemistry methods that can be used to treat the QM subsystem. We review the coupling strategy between the QM subsystem and the APE, which requires to examine the way the QM/MM mutual interactions are accounted for and how the polarization of the classical environment is considered with respect to (wrt) the quantum variables. Because of the need of reliable molecular and macromolecular structures, a pivotal aspect to address here is the handling of the system dynamics (i.e., gradients wrt nuclear positions are required), especially for large molecular assemblies composed by an overwhelming number of atoms, exploring many conformations on a complex energy landscape.Alongside, we highlight our views on the necessary steps to take toward more accurate general-purposes and transferable explicit embeddings. The main objective to achieve here is to design a more physically grounded multiscale approach. To do so, one should apply advanced new generation classical models to account for refined induction effects that are able to (i) improve the quality of QM/MM interaction energies; (ii) enhance transferability by avoiding the compulsory partial (or total) reparameterization of the classical model. Moreover, the extension of recent developments originating from the field of advanced classical molecular dynamics (MD) to the realm of QM/APE methods is a key direction to improve both speed and efficiency for the phase space exploration of systems of growing size and complexity.Lastly, we point out specific research topics where an advanced QM/APE dynamics can certainly shed some light. For example, we discuss chemical reactions in "harsh" environments and the case of spectroscopic theoretical modeling where the inclusion of refined environment effects is often mandatory.

Efficient and Accurate Description of Diels-Alder Reactions Using Density Functional Theory.

Modeling chemical reactions using Quantum Chemistry is a widely used predictive strategy capable to complement experiments in order to understand the intrinsic mechanisms guiding the chemicals towards the most favorable reaction products. However, at this purpose, it is mandatory to use reliable and computationally tractable theoretical methods. In this work, we focus on six Diels-Alder reactions of increasing complexity and perform an extensive benchmark of middle- to low-cost computational approaches to predict the characteristic reactions energy barriers. We found that Density Functional Theory, using the ωB97XD, LC-ωPBE, CAM-B3LYP, M11 and MN12SX functionals, with empirical dispersion corrections coupled to an affordable 6-31G basis set, provides quality results for this class of reactions, at a small computational effort. Such efficient and reliable simulation protocol opens perspectives for hybrid QM/MM molecular dynamics simulations of Diels-Alder reactions including explicit solvation.

Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators.

GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side chain on both arms. The anthraquinone ring is intercalated in the central d(CpG)2 sequence with its long axis perpendicular to that of the two base pairs. On each strand, this enables each ammonium group to bind in-register to O6/N7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N9-aminoacridine intercalator extending our target range from a six- to a ten-base-pair palindromic sequence, d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most promising derivative are reported. The present design strategy paves the way for designing intercalator-oligopeptide derivatives with even higher selectivity, targeting an increased number of DNA bases, going beyond ten.

Molecular Dynamics Simulations of Ionic Liquids and Electrolytes Using Polarizable Force Fields.

Many applications in chemistry, biology, and energy storage/conversion research rely on molecular simulations to provide fundamental insight into structural and transport properties of materials with high ionic concentrations. Whether the system is comprised entirely of ions, like ionic liquids, or is a mixture of a polar solvent with a salt, e.g., liquid electrolytes for battery applications, the presence of ions in these materials results in strong local electric fields polarizing solvent molecules and large ions. To predict properties of such systems from molecular simulations often requires either explicit or mean-field inclusion of the influence of polarization on electrostatic interactions. In this manuscript, we review the pros and cons of different treatments of polarization ranging from the mean-field approaches to the most popular explicit polarization models in molecular dynamics simulations of ionic materials. For each method, we discuss their advantages and disadvantages and emphasize key assumptions as well as their adjustable parameters. Strategies for the development of polarizable models are presented with a specific focus on extracting atomic polarizabilities. Finally, we compare simulations using polarizable and nonpolarizable models for several classes of ionic systems, discussing the underlying physics that each approach includes or ignores, implications for implementation and computational efficiency, and the accuracy of properties predicted by these methods compared to experiments.

Improvement of the Gaussian Electrostatic Model by separate fitting of Coulomb and exchange-repulsion densities and implementation of a new dispersion term.

The description of each separable contribution of the intermolecular interaction is a useful approach to develop polarizable force fields (polFFs). The Gaussian Electrostatic Model (GEM) is based on this approach, coupled with the use of density fitting techniques. In this work, we present the implementation and testing of two improvements of GEM: the Coulomb and exchange-repulsion energies are now computed with separate frozen molecular densities and a new dispersion formulation inspired by the Sum of Interactions Between Fragments Ab initio Computed polFF, which has been implemented to describe the dispersion and charge-transfer interactions. Thanks to the combination of GEM characteristics and these new features, we demonstrate a better agreement of the computed structural and condensed properties for water with experimental results, as well as binding energies in the gas phase with the ab initio reference compared with the previous GEM* potential. This work provides further improvements to GEM and the items that remain to be improved and the importance of the accurate reproduction for each separate contribution.

On the Quantum Chemical Nature of Lead(II) "Lone Pair".

We study the quantum chemical nature of the Lead(II) valence basins, sometimes called the lead "lone pair". Using various chemical interpretation tools, such as molecular orbital analysis, natural bond orbitals (NBO), natural population analysis (NPA) and electron localization function (ELF) topological analysis, we study a variety of Lead(II) complexes. A careful analysis of the results shows that the optimal structures of the lead complexes are only governed by the 6s and 6p subshells, whereas no involvement of the 5d orbitals is found. Similarly, we do not find any significant contribution of the 6d. Therefore, the Pb(II) complexation with its ligand can be explained through the interaction of the 6s2 electrons and the accepting 6p orbitals. We detail the potential structural and dynamical consequences of such electronic structure organization of the Pb (II) valence domain.

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase.

We calibrate and validate the parameters necessary to represent the dianionic phosphate group (DPG) in molecular mechanics. DPG is an essential fragment of signaling biological molecules and protein-binding ligands. It is a constitutive fragment of biosensors, which bind to the dimer interface of phosphoglucose isomerase (PGI), an intracellular enzyme involved in sugar metabolism, as well as an extracellular protein known as autocrine motility factor (AMF) closely related to metastasis formation. Our long-term objective is to design DPG-based biosensors with enhanced affinities for AMF/PGI cancer biomarker in blood. Molecular dynamics with polarizable potentials could be used toward this aim. This requires to first evaluate the accuracy of such potentials upon representing the interactions of DPG with its PGI ligands and tightly bound water molecules. Such evaluations are done by comparisons with high-level ab initio quantum chemistry (QC) calculations. We focus on the Sum of Interactions Between Fragments Ab initio computed (SIBFA) polarizable molecular mechanics procedure. We present first the results of the DPG calibration. This is followed by comparisons between ΔE(SIBFA) and ΔE(QC) regarding bi-molecular complexes of DPG with the main-chain and side-chain PGI residues, which bind to it in the recognition site. We then consider DPG complexes with an increasing number of PGI residues. The largest QC complexes encompass the entirety of the recognition site, with six structural water molecules totaling up to 211 atoms. A persistent and satisfactory agreement could be shown between ΔE(SIBFA) and ΔE(QC). These validations constitute an essential first step toward large-scale molecular dynamics simulations of DPG-based biosensors bound at the PGI dimer interface. © 2020 Wiley Periodicals, Inc.

New Way for Probing Bond Strength.

The covalent chemical bond is intimately linked to electron sharing between atoms. The recent independent gradient model (IGM) and its δg descriptor provide a way to quantify locally this electron density interpenetration from wavefunction calculations. Each bond has its own IGM-δgpair signature. The present work establishes for the first time a strong link between this bond signature and the physically grounded bond force constant concept. Analyzing a large set of compounds and bonds, the intrinsic bond strength index (IBSI) emerges from the IGM formulation. Our study shows that the IBSI does not belong to the class of conventional bond orders (like Mulliken, Wiberg, Mayer, delocalization index, or electron localization function-ELF), but is rather a new complementary index, related to the bond strength. A fundamental outcome of this research is a novel index allowing to range all two-center chemical bonds by their intrinsic strength in molecular situation. We believe that the IBSI is a powerful and robust tool for interpretation accessible to a wide community of chemists (organic, inorganic chemistry, including transition-metal complexes and reaction mechanisms).

Velocity jump processes: An alternative to multi-timestep methods for faster and accurate molecular dynamics simulations.

We propose a new route to accelerate molecular dynamics through the use of velocity jump processes allowing for an adaptive time step specific to each atom-atom pair (two-body) interactions. We start by introducing the formalism of the new velocity jump molecular dynamics, ergodic with respect to the canonical measure. We then introduce the new BOUNCE integrator that allows for long-range forces to be evaluated at random and optimal time steps, leading to strong savings in direct space. The accuracy and computational performances of a first BOUNCE implementation dedicated to classical (non-polarizable) force fields are tested in the cases of pure direct-space droplet-like simulations and of periodic boundary conditions (PBC) simulations using Smooth Particle Mesh Ewald method. An analysis of the capability of BOUNCE to reproduce several condensed-phase properties is provided. Since electrostatics and van der Waals two-body contributions are evaluated much less often than with standard integrators using a 1 fs time step, up to a 400% direct-space acceleration is observed. Applying the reversible reference system propagator algorithms [RESPA(1)] to reciprocal-space (many-body) interactions allows BOUNCE-RESPA(1) to maintain large speedups in PBC while maintaining precision. Overall, we show that replacing the BAOAB standard Langevin integrator by the BOUNCE adaptive framework preserves a similar accuracy and leads to significant computational savings.

The Independent Gradient Model: A New Approach for Probing Strong and Weak Interactions in Molecules from Wave Function Calculations.

Extraction of the chemical interaction signature from local descriptors based on electron density (ED) is still a fruitful field of development in chemical interpretation. In a previous work that used promolecular ED (frozen ED), the new descriptor, δg , was defined. It represents the difference between a virtual upper limit of the ED gradient (∇ρIGM , IGM=independent gradient model) that represents a noninteracting system and the true ED gradient (∇ρ ). It can be seen as a measure of electron sharing brought by ED contragradience. A compelling feature of this model is to provide an automatic workflow that extracts the signature of interactions between selected groups of atoms. As with the noncovalent interaction (NCI) approach, it provides chemists with a visual understanding of the interactions present in chemical systems. ∇ρIGM is achieved simply by using absolute values upon summing the individual gradient contributions that make up the total ED gradient. Hereby, we extend this model to relaxed ED calculated from a wave function. To this end, we formulated gradient-based partitioning (GBP) to assess the contribution of each orbital to the total ED gradient. We highlight these new possibilities across two prototypical examples of organic chemistry: the unconventional hexamethylbenzene dication, with a hexa-coordinated carbon atom, and ß-thioaminoacrolein. It will be shown how a bond-by-bond picture can be obtained from a wave function, which opens the way to monitor specific interactions along reaction paths.

A coherent derivation of the Ewald summation for arbitrary orders of multipoles: The self-terms.

In this work, we provide the mathematical elements we think essential for a proper understanding of the calculus of the electrostatic energy of point-multipoles of arbitrary order under periodic boundary conditions. The emphasis is put on the expressions of the so-called self-parts of the Ewald summation where different expressions can be found in the literature. Indeed, such expressions are of prime importance in the context of new generation polarizable force field where the self-field appears in the polarization equations. We provide a general framework, where the idea of the Ewald splitting is applied to the electric potential and, subsequently, all other quantities such as the electric field, the energy, and the forces are derived consistently thereof. Mathematical well-posedness is shown for all these contributions for any order of multipolar distribution.

The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir.

The Human Immunodeficiency Virus-1 integrase is responsible for the covalent insertion of a newly synthesized double-stranded viral DNA into the host cells, and is an emerging target for antivirus drug design. Raltegravir (RAL) and elvitegravir (EVG) are the first two integrase strand transfer inhibitors used in therapy. However, treated patients eventually develop detrimental resistance mutations. By contrast, a recently approved drug, dolutegravir (DTG), presents a high barrier to resistance. This study aims to understand the increased efficiency of DTG upon focusing on its interaction properties with viral DNA. The results showed DTG to be involved in more extended interactions with viral DNA than EVG. Such interactions involve the halobenzene and scaffold of DTG and EVG and bases 5'G-43', 3'A35'and 3'C45'.

Tinker-OpenMM: Absolute and relative alchemical free energies using AMOEBA on GPUs.

The capabilities of the polarizable force fields for alchemical free energy calculations have been limited by the high computational cost and complexity of the underlying potential energy functions. In this work, we present a GPU-based general alchemical free energy simulation platform for polarizable potential AMOEBA. Tinker-OpenMM, the OpenMM implementation of the AMOEBA simulation engine has been modified to enable both absolute and relative alchemical simulations on GPUs, which leads to a ∼200-fold improvement in simulation speed over a single CPU core. We show that free energy values calculated using this platform agree with the results of Tinker simulations for the hydration of organic compounds and binding of host-guest systems within the statistical errors. In addition to absolute binding, we designed a relative alchemical approach for computing relative binding affinities of ligands to the same host, where a special path was applied to avoid numerical instability due to polarization between the different ligands that bind to the same site. This scheme is general and does not require ligands to have similar scaffolds. We show that relative hydration and binding free energy calculated using this approach match those computed from the absolute free energy approach. © 2017 Wiley Periodicals, Inc.

Importance of explicit smeared lone-pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange-repulsion and charge transfer contributions.

A correct representation of the short-range contributions such as exchange-repulsion (Erep ) and charge-transfer (Ect ) is essential for the soundness of separable, anisotropic polarizable molecular mechanics potentials. Within the context of the SIBFA procedure, this is aimed at by explicit representations of lone pairs in their expressions. It is necessary to account for their anisotropic behaviors upon performing not only in-plane, but also out-of-plane, variations of a probe molecule or cation interacting with a target molecule or molecular fragment. Thus, Erep and Ect have to reproduce satisfactorily the corresponding anisotropies of their quantum chemical (QC) counterparts. A significant improvement of the out-of-plane dependencies was enabled when the sp2 and sp localized lone-pairs are, even though to a limited extent, delocalized on both sides of the plane, above and below the atom bearer but at the closely similar angles as the in-plane lone pair. We report calibration and validation tests on a series of monoligated complexes of a probe Zn(II) cation with several biochemically relevant ligands. Validations are then performed on several polyligated Zn(II) complexes found in the recognition sites of Zn-metalloproteins. Such calibrations and validations are extended to representative monoligated and polyligated complexes of Mg(II) and Ca(II). It is emphasized that the calibration of all three cations was for each ΔE contribution done on a small training set bearing on a limited number of representative N, O, and S monoligated complexes. Owing to the separable nature of ΔE, a secure transferability is enabled to a diversity of polyligated complexes. For these the relative errors with respect to the target ΔE(QC) values are generally < 3%. Overall, the article proposes a full set of benchmarks that could be useful for force field developers. © 2017 Wiley Periodicals, Inc.

Preface: Special Topic: From Quantum Mechanics to Force Fields.

This Special Topic issue entitled "From Quantum Mechanics to Force Fields" is dedicated to the ongoing efforts of the theoretical chemistry community to develop a new generation of accurate force fields based on data from high-level electronic structure calculations and to develop faster electronic structure methods for testing and designing force fields as well as for carrying out simulations. This issue includes a collection of 35 original research articles that illustrate recent theoretical advances in the field. It provides a timely snapshot of recent developments in the generation of approaches to enable more accurate molecular simulations of processes important in chemistry, physics, biophysics, and materials science.

The truncated conjugate gradient (TCG), a non-iterative/fixed-cost strategy for computing polarization in molecular dynamics: Fast evaluation of analytical forces.

In a recent paper [F. Aviat et al., J. Chem. Theory Comput. 13, 180-190 (2017)], we proposed the Truncated Conjugate Gradient (TCG) approach to compute the polarization energy and forces in polarizable molecular simulations. The method consists in truncating the conjugate gradient algorithm at a fixed predetermined order leading to a fixed computational cost and can thus be considered "non-iterative." This gives the possibility to derive analytical forces avoiding the usual energy conservation (i.e., drifts) issues occurring with iterative approaches. A key point concerns the evaluation of the analytical gradients, which is more complex than that with a usual solver. In this paper, after reviewing the present state of the art of polarization solvers, we detail a viable strategy for the efficient implementation of the TCG calculation. The complete cost of the approach is then measured as it is tested using a multi-time step scheme and compared to timings using usual iterative approaches. We show that the TCG methods are more efficient than traditional techniques, making it a method of choice for future long molecular dynamics simulations using polarizable force fields where energy conservation matters. We detail the various steps required for the implementation of the complete method by software developers.