Theoretical Prediction of Hydrogen-Bond Basicity pKBHX Using Quantum Chemical Topology Descriptors

[Image: see text] Hydrogen bonding plays an important role in the interaction of biological molecules and their local environment. Hydrogen-bond strengths have been described in terms of basicities by several different scales. The pK(BHX) scale has been developed with the interests of medicinal chemists in mind. The scale uses equilibrium constants of acid···base complexes to describe basicity and is therefore linked to Gibbs free energy. Site specific data for polyfunctional bases are also available. The pK(BHX) scale applies to all hydrogen-bond donors (HBDs) where the HBD functional group is either OH, NH, or NH(+). It has been found that pK(BHX) can be described in terms of a descriptor defined by quantum chemical topology, ΔE(H), which is the change in atomic energy of the hydrogen atom upon complexation. Essentially the computed energy of the HBD hydrogen atom correlates with a set of 41 HBAs for five common HBDs, water (r(2) = 0.96), methanol (r(2) = 0.95), 4-fluorophenol (r(2) = 0.91), serine (r(2) = 0.93), and methylamine (r(2) = 0.97). The connection between experiment and computation was strengthened with the finding that there is no relationship between ΔE(H) and pK(BHX) when hydrogen fluoride was used as the HBD. Using the methanol model, pK(BHX) predictions were made for an external set of bases yielding r(2) = 0.90. Furthermore, the basicities of polyfunctional bases correlate with ΔE(H), giving r(2) = 0.93. This model is promising for the future of computation in fragment-based drug design. Not only has a model been established that links computation to experiment, but the model may also be extrapolated to predict external experimental pK(BHX) values

How to Compute Atomistic Insight in DFT clusters: the REG-IQA Approach

<p>Dataset for the paper "How to Compute Atomistic Insight in DFT clusters: the REG-IQA Approach" published to<i> Journal of Chemical Information and Modelling</i>.</p><p>The Dataset contains all the AIMAll calculations for each step of the intrinsic reaction coordinate of the HIV Protease hydrolysis described in the main manuscript and .xlsx files for all the REG-IQA results of the analyses pursued.</p&gt

DL_FFLUX: a parallel, quantum chemical topology force field

DL_FFLUX is a force field based on quantum chemical topology that can perform molecular dynamics for flexible molecules endowed with polarisable atomic multipole moments (up to hexadecapole). Using the machine learning method kriging (aka Gaussian Process Regression) DL_FFLUX has access to atomic properties (energy, charge, dipole moment, …) with quantum mechanical accuracy. Newly optimised and parallelised using domain-decomposition MPI, DL_FFLUX is now able to deliver this rigorous methodology at scale while still in reasonable time frames. DL_FFLUX is delivered as an add-on to the widely distributed molecular dynamics code DL_POLY 4.08. For the systems studied here (103-105 atoms), DL_FFLUX is shown to add minimal computational cost to the standard DL_POLY package. In fact, the optimisation of the electrostatics in DL_FFLUX means that, when high rank multipole moments are enabled, DL_FFLUX is up to 1.25x faster than standard DL_POLY. The parallel DL_FFLUX preserves the quality of the scaling of the MPI implementation in standard DL_POLY. For the first time it is feasible to use the full capability of DL_FFLUX to study systems that are large enough to be of real world interest. For example, a fully flexible, high-rank polarised (up to and including quadrupole moments) 1 ns simulation of a system of 10,125 atoms (3,375 water molecules) takes 30 hours (wall time) on 18 cores

Towards an Atomistic Understanding of Polymorphism in Molecular Solids

Many chemical phenomena are ultimately due to energy balances between atoms. In order to reach firm and clear conclusions one needs a reliable energy decomposition analysis (EDA). The Interacting Quantum Atoms (IQA) energy partitioning method is one of the most recent EDA methods. IQA is a topological energy partitioning that generates well-defined intra- and interatomic contributions, of steric, electrostatic or covalent (exchange) character. IQA has a minimal and powerful architecture and does not suffer from a number of conceptual and practical problems that plague the more traditional non-topological EDAs (Chem. Soc. Rev., 44 (2015) 3177).For the first time, our manuscript reports on a protocol for using the IQA to understand polymorphism, which we apply to the three polymorphs of succinic acid (SA), including the unusual polymorph that was recently discovered serendipitously (CrystEngComm, 20 (2018) 3971). The many intra- and interatomic energy terms from the EDA scheme are processed using a new technique that we developed called the Relative Energy Gradient (REG) method, which clearly identifies the atoms and corresponding energetic terms that govern the behaviour of the total system, in a minimal and unbiased way. </div

Substituent effects on the basicity (pKa) of aryl Q1 guanidines and 2-(arylimino)imidazolidines: correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths

The dissociation constants of two related series of 2-(arylimino)imidazolidine and aryl guanidine α-adrenoceptor antagonists (35 compounds in total) were measured by potentiometric titrations and by UV-spectrophotometry using the 96-well microtitre plate method. The experimental values obtained using both methods were quite consistent and showed a very good agreement with the pK values calculated using the AIBLHiCoS methodology, which uses only a single bond length obtained using ab initio calculations at a low level of theory. The prediction power of the imidazolidine and guanidine set of compounds was very good with deviations typically <0.30 and <0.24 pK units, and a mean absolute error (MAE) of 0.23 and 0.29, respectively. The study of the quantitative effect of diverse substituents on the basicity of aryl guanidine and 2-(arylimino)imidazolidine derivatives is useful for medicinal chemists working with biologically relevant guanidine-containing molecules.This work was supported by the Spanish Ministerio de Economia y Competitividad (Grant SAF2015-66690-R). B. A. Caine thanks BBSRC and Syngenta Ltd for PhD funding. P. L. A. P. acknowledges the EPSRC for funding through the award of an Established Career Fellowship (grant EP/K005472). We acknowledge the assistance of G. Romero and F. Peréz Gordillo (Instrumental Analysis Department at IQM) with the potentiometric pKa measurements. We thank Chanse`le Jourdan for her assistance with the UV-metric pKa measurements. Dr Rozas is gratefully acknowledged for the gift of the pyridino derivatives 16–22 and the Boc-protected precursors of compounds 1–10 and 23–27.Peer Reviewe