Nonbonded Force Field Parameters from MBIS Partitioning of the Molecular Electron Density Improve Binding Affinity Predictions of the T4-Lysozyme Double Mutant.

The use of computer simulation for binding affinity prediction is growing in drug discovery. However, its wider use is constrained by the accuracy of the free energy calculations. The key sources of error are the force fields used to depict molecular interactions and insufficient sampling of the configurational space. To improve the quality of the force field, we developed a Python-based computational workflow. The workflow described here uses the minimal basis iterative stockholder (MBIS) method to determine atomic charges and Lennard-Jones parameters from the polarized molecular density. This is done by performing electronic structure calculations on various configurations of the ligand when it is both bound and unbound. In addition, we validated a simulation procedure that accounts for the protein and ligand degrees of freedom to precisely calculate binding free energies. This was achieved by comparing the self-adjusted mixture sampling and nonequilibrium thermodynamic integration methods using various protein and ligand conformations. The accuracy of predicting binding affinity is improved by using MBIS-derived force field parameters and a validated simulation procedure. This improvement surpasses the chemical precision for the eight aromatic ligands, reaching a root-mean-square error of 0.7 kcal/mol.

The tale of HORTON: Lessons learned in a decade of scientific software development.

HORTON is a free and open-source electronic-structure package written primarily in Python 3 with some underlying C++ components. While HORTON's development has been mainly directed by the research interests of its leading contributing groups, it is designed to be easily modified, extended, and used by other developers of quantum chemistry methods or post-processing techniques. Most importantly, HORTON adheres to modern principles of software development, including modularity, readability, flexibility, comprehensive documentation, automatic testing, version control, and quality-assurance protocols. This article explains how the principles and structure of HORTON have evolved since we started developing it more than a decade ago. We review the features and functionality of the latest HORTON release (version 2.3) and discuss how HORTON is evolving to support electronic structure theory research for the next decade.

Grid: A Python library for molecular integration, interpolation, differentiation, and more.

Grid is a free and open-source Python library for constructing numerical grids to integrate, interpolate, and differentiate functions (e.g., molecular properties), with a strong emphasis on facilitating these operations in computational chemistry and conceptual density functional theory. Although designed, maintained, and released as a stand-alone Python library, Grid was originally developed for molecular integration, interpolation, and solving the Poisson equation in the HORTON and ChemTools packages. Grid is designed to be easy to use, extend, and maintain; this is why we use Python and adopt many principles of modern software development, including comprehensive documentation, extensive testing, continuous integration/delivery protocols, and package management. We leverage popular scientific packages, such as NumPy and SciPy, to ensure high efficiency and optimized performance in grid development. This article is the official release note of the Grid library showcasing its unique functionality and scope.

Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP+-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP+ and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP+-binding site that is crucial for stabilization and ordering two ß-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency.

Conformational Dynamics of the Most Efficient Carboxylase Contributes to Efficient CO2 Fixation.

Crotonyl-CoA carboxylase/reductase (Ccr) is one of the fastest CO2 fixing enzymes and has become part of efficient artificial CO2-fixation pathways in vitro, paving the way for future applications. The underlying mechanism of its efficiency, however, is not yet completely understood. X-ray structures of different intermediates in the catalytic cycle reveal tetramers in a dimer of dimers configuration with two open and two closed active sites. Upon binding a substrate, this active site changes its conformation from the open state to the closed state. It is challenging to predict how these coupled conformational changes will alter the CO2 binding affinity to the reaction's active site. To determine whether the open or closed conformations of Ccr affect binding of CO2 to the active site, we performed all-atom molecular simulations of the various conformations of Ccr. The open conformation without a substrate showed the highest binding affinity. The CO2 binding sites are located near the catalytic relevant Asn81 and His365 residues and in an optimal position for CO2 fixation. Furthermore, they are unaffected by substrate binding, and CO2 molecules stay in these binding sites for a longer time. Longer times at these reactive binding sites facilitate CO2 fixation through the nucleophilic attack of the reactive enolate in the closed conformation. We previously demonstrated that the Asn81Leu variant cannot fix CO2. Simulations of the Asn81Leu variant explain the loss of activity through the removal of the Asn81 and His365 binding sites. Overall, our findings show that the conformational dynamics of the enzyme controls CO2 binding. Conformational changes in Ccr increase the level of CO2 in the open subunit before the substrate is bound, the active site closes, and the reaction starts. The full catalytic Ccr cycle alternates among CO2 addition, conformational change, and chemical reaction in the four subunits of the tetramer coordinated by communication between the two dimers.

Ene-adducts from 1,4-dihydropyridines and α,ß-unsaturated nitriles: asynchronous transition states displaying aromatic features.

Hydride transfer reactions involving 1,4-dihydropyridines play a central role in bioorganic chemistry as they represent an important share of redox metabolism. For this class of reactions, direct hydride transfer is the commonly accepted mechanism; however, an Alder-Ene-like pathway has been proposed as a plausible alternative. The reaction between 1,4-ditrimethylsilyl-1,4-dihydropyridine and α,ß-unsaturated nitriles is a solid candidate for this latter pathway. In this work, we perform high level ab initio and density functional theory computations to characterize the mechanism of this reaction, taking into account diverse reaction paths, and evaluating the effect of solvent polarity and variations in the chemical structure. Our analysis explains the stereochemical aspects of the reaction, characterizing the up to now unresolved spatial configurations of the predominant products, and may contribute to the understanding of enzymatic reactions involving NADP(H). The reactions are found to proceed in an asynchronous fashion, with transition states that display significant aromatic features. With this observation in mind, Alder-Ene and direct hydride transfer pathways can be understood as two extremes of a continuous mechanistic spectrum for this kind of reaction, with the analyzed systems located approximately equidistant from both ends.

Nonbonded Force Field Parameters from Minimal Basis Iterative Stockholder Partitioning of the Molecular Electron Density Improve CB7 Host-Guest Affinity Predictions.

Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.

Constrained iterative Hirshfeld charges: A variational approach.

We develop a variational procedure for the iterative Hirshfeld (HI) partitioning scheme. The main practical advantage of having a variational framework is that it provides a formal and straightforward approach for imposing constraints (e.g., fixed charges on certain atoms or molecular fragments) when computing HI atoms and their properties. Unlike many other variants of the Hirshfeld partitioning scheme, HI charges do not arise naturally from the information-theoretic framework, but only as a reverse-engineered construction of the objective function. However, the procedure we use is quite general and could be applied to other problems as well. We also prove that there is always at least one solution to the HI equations, but we could not prove that its self-consistent equations would always converge for any given initial pro-atom charges. Our numerical assessment of the constrained iterative Hirshfeld method shows that it satisfies many desirable traits of atoms in molecules and has the potential to surpass existing approaches for adding constraints when computing atomic properties.

Four amino acids define the CO2 binding pocket of enoyl-CoA carboxylases/reductases.

Carboxylases are biocatalysts that capture and convert carbon dioxide (CO2) under mild conditions and atmospheric concentrations at a scale of more than 400 Gt annually. However, how these enzymes bind and control the gaseous CO2 molecule during catalysis is only poorly understood. One of the most efficient classes of carboxylating enzymes are enoyl-CoA carboxylases/reductases (Ecrs), which outcompete the plant enzyme RuBisCO in catalytic efficiency and fidelity by more than an order of magnitude. Here we investigated the interactions of CO2 within the active site of Ecr from Kitasatospora setae Combining experimental biochemistry, protein crystallography, and advanced computer simulations we show that 4 amino acids, N81, F170, E171, and H365, are required to create a highly efficient CO2-fixing enzyme. Together, these 4 residues anchor and position the CO2 molecule for the attack by a reactive enolate created during the catalytic cycle. Notably, a highly ordered water molecule plays an important role in an active site that is otherwise carefully shielded from water, which is detrimental to CO2 fixation. Altogether, our study reveals unprecedented molecular details of selective CO2 binding and C-C-bond formation during the catalytic cycle of nature's most efficient CO2-fixing enzyme. This knowledge provides the basis for the future development of catalytic frameworks for the capture and conversion of CO2 in biology and chemistry.

IOData: A python library for reading, writing, and converting computational chemistry file formats and generating input files.

IOData is a free and open-source Python library for parsing, storing, and converting various file formats commonly used by quantum chemistry, molecular dynamics, and plane-wave density-functional-theory software programs. In addition, IOData supports a flexible framework for generating input files for various software packages. While designed and released for stand-alone use, its original purpose was to facilitate the interoperability of various modules in the HORTON and ChemTools software packages with external (third-party) molecular quantum chemistry and solid-state density-functional-theory packages. IOData is designed to be easy to use, maintain, and extend; this is why we wrote IOData in Python and adopted many principles of modern software development, including comprehensive documentation, extensive testing, continuous integration/delivery protocols, and package management. This article is the official release note of the IOData library.

Molecular Environment-Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems.

Host-guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field. Here, we propose a new methodology to derive the atomic charges of host-guest systems based on quantum mechanics/molecular mechanics calculations and minimal basis iterative stockholder (MBIS) partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software packages provides D-MBIS charges that represent the guest's average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the general Amber force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction originates from the difference in potential energy that is required to polarize the guest in the bound and unbound state and contributes significantly to the binding affinity of anionic guests.

Electronic structure benchmark calculations of CO2 fixing elementary chemical steps in RuBisCO using the projector-based embedding approach.

Ribulose 1,5-bisphosphate carboxylase-oxygenase (RuBisCO) is the main enzyme involved in atmospheric carbon dioxide (CO2 ) fixation in the biosphere. This enzyme catalyzes a set of five chemical steps that take place in the same active-site within magnesium (II) coordination sphere. Here, a set of electronic structure benchmark calculations have been carried out on a reaction path proposed by Gready et al. by means of the projector-based embedding approach. Activation and reaction energies for all main steps catalyzed by RuBisCO have been calculated at the MP2, SCS-MP2, CCSD, and CCSD(T)/aug-cc-pVDZ and cc-pVDZ levels of theory. The treatment of the magnesium cation with post-HF methods is explored to determine the nature of its involvement in the mechanism. With the high-level ab initio values as a reference, we tested the performance of a set of density functional theory (DFT) exchange-correlation (xc) functionals in reproducing the reaction energetics of RuBisCO carboxylase activity on a set of model fragments. Different DFT xc-functionals show large variation in activation and reaction energies. Activation and reaction energies computed at the B3LYP level are close to the reference SCS-MP2 results for carboxylation, hydration and protonation reactions. However, for the carbon-carbon bond dissociation reaction, B3LYP and other functionals give results that differ significantly from the ab initio reference values. The results show the applicability of the projector-based embedding approach to metalloenzymes. This technique removes the uncertainty associated with the selection of different DFT xc-functionals and so can overcome some of inherent limitations of DFT calculations, complementing, and potentially adding to modeling of enzyme reaction mechanisms with DFT methods.

SAMPL6 Octanol-water partition coefficients from alchemical free energy calculations with MBIS atomic charges.

In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of 11 molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder (MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed.

Atom-Condensed Fukui Function in Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide.

Local reactivity descriptors such as atom-condensed Fukui functions are promising computational tools to study chemical reactivity at specific sites within a molecule. Their applications have been mainly focused on isolated molecules in their most stable conformation without considering the effects of the surroundings. Here we propose to combine quantum mechanics/molecular mechanics Born-Oppenheimer molecular dynamics simulations to obtain the microstates (configurations) of a molecular system using different representations of the molecular environment and calculate Boltzmann-weighted atom-condensed local reactivity descriptors based on conceptual density functional theory. Our approach takes the conformational fluctuations of the molecular system and the polarization of its electron density by the environment into account, allowing us to analyze the effect of the molecular environment on reactivity. In this contribution, we apply the method mentioned above to the catalytic fixation of carbon dioxide by crotonyl-CoA carboxylase/reductase and study if the enzyme alters the reactivity of its substrate compared with an aqueous solution. Our main result is that the protein environment activates the substrate by the elimination of solute-solvent hydrogen bonds from aqueous solution in the two elementary steps of the reaction mechanism: the nucleophilic attack of a hydride anion from NADPH on the α,ß-unsaturated thioester and the electrophilic attack of carbon dioxide on the formed enolate species.

Conformational sampling and polarization of Asp26 in pKa calculations of thioredoxin.

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (eg, Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation, the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations. The varying polarization of the two residues in different molecular environments and protonation states is described by Hirshfeld-I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighboring Lys57 residue orientations and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of the polarization of both aspartate residues in the free energy cycle by HI atomic charges corrects the results from the non-polarizable force field and reproduces the experimental ΔpKa value of Asp26.

Awakening the Sleeping Carboxylase Function of Enzymes: Engineering the Natural CO2-Binding Potential of Reductases.

Developing new carbon dioxide (CO2) fixing enzymes is a prerequisite to create new biocatalysts for diverse applications in chemistry, biotechnology and synthetic biology. Here we used bioinformatics to identify a "sleeping carboxylase function" in the superfamily of medium-chain dehydrogenases/reductases (MDR), i.e. enzymes that possess a low carboxylation side activity next to their original enzyme reaction. We show that propionyl-CoA synthase from Erythrobacter sp. NAP1, as well as an acrylyl-CoA reductase from Nitrosopumilus maritimus possess carboxylation yields of 3 ± 1 and 4.5 ± 0.9%. We use rational design to engineer these enzymes further into carboxylases by increasing interactions of the proteins with CO2 and suppressing diffusion of water to the active site. The engineered carboxylases show improved CO2-binding and kinetic parameters comparable to naturally existing CO2-fixing enzymes. Our results provide a strategy to develop novel CO2-fixing enzymes and shed light on the emergence of natural carboxylases during evolution.

Electronic structure benchmark calculations of inorganic and biochemical carboxylation reactions.

Carboxylation reactions represent a very special class of chemical reactions that is characterized by the presence of a carbon dioxide (CO2 ) molecule as reactive species within its global chemical equation. These reactions work as fundamental gear to accomplish the CO2 fixation and thus to build up more complex molecules through different technological and biochemical processes. In this context, a correct description of the CO2 electronic structure turns out to be crucial to study the chemical and electronic properties associated with this kind of reactions. Here, a systematic study of CO2 electronic structure and its contribution to different carboxylation reaction electronic energies has been carried out by means of several high-level ab initio post-Hartree Fock (post-HF) and density functional theory (DFT) calculations for a set of biochemistry and inorganic systems. We have found that for a correct description of the CO2 electronic correlation energy it is necessary to include post-CCSD(T) contributions (beyond the gold standard). These high-order excitations are required to properly describe the interactions of the four π-electrons associated with the two degenerated π-molecular orbitals of the CO2 molecule. Likewise, our results show that in some reactions it is possible to obtain accurate reaction electronic energy values with computationally less demanding methods when the error in the electronic correlation energy compensates between reactants and products. Furthermore, the provided post-HF reference values allowed to validating different DFT exchange-correlation functionals combined with different basis sets for chemical reactions that are relevant in biochemical CO2 fixing enzymes. © 2019 Wiley Periodicals, Inc.

Hydration Free Energies in the FreeSolv Database Calculated with Polarized Iterative Hirshfeld Charges.

Computer simulations of biomolecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in biomolecular systems and are therein described by atomic point charges. In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute's electron density computed with an implicit solvent model, and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the AM1-BCC and the MBIS atomic charge methods. The latter includes the solvent polarization and presents a root-mean-square error of 2.0 kcal mol-1 for the 613 organic molecules studied. The largest deviation was observed for phosphorus-containing molecules and the molecules with amide, ester and amine functional groups.

Information-Theoretic Approaches to Atoms-in-Molecules: Hirshfeld Family of Partitioning Schemes.

Many population analysis methods are based on the precept that molecules should be built from fragments (typically atoms) that maximally resemble the isolated fragment. The resulting molecular building blocks are intuitive (because they maximally resemble well-understood systems) and transferable (because if two molecular fragments both resemble an isolated fragment, they necessarily resemble each other). Information theory is one way to measure the deviation between molecular fragments and their isolated counterparts, and it is a way that lends itself to interpretation. For example, one can analyze the relative importance of electron transfer and polarization of the fragments. We present key features, advantages, and disadvantages of the information-theoretic approach. We also codify existing information-theoretic partitioning methods in a way that clarifies the enormous freedom one has within the information-theoretic ansatz.

Communication: Photoinduced carbon dioxide binding with surface-functionalized silicon quantum dots.

Nowadays, the search for efficient methods able to reduce the high atmospheric carbon dioxide concentration has turned into a very dynamic research area. Several environmental problems have been closely associated with the high atmospheric level of this greenhouse gas. Here, a novel system based on the use of surface-functionalized silicon quantum dots (sf-SiQDs) is theoretically proposed as a versatile device to bind carbon dioxide. Within this approach, carbon dioxide trapping is modulated by a photoinduced charge redistribution between the capping molecule and the silicon quantum dots (SiQDs). The chemical and electronic properties of the proposed SiQDs have been studied with a Density Functional Theory and Density Functional Tight-Binding (DFTB) approach along with a time-dependent model based on the DFTB framework. To the best of our knowledge, this is the first report that proposes and explores the potential application of a versatile and friendly device based on the use of sf-SiQDs for photochemically activated carbon dioxide fixation.