Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

Computational analysis of protein–ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions, such as in docking programs, all rely on equations that sum each type of protein–ligand interactions in order to predict the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions constitute one of the most important part of total interactions between macromolecules. Unlike dispersion forces, they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this study, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and darunavir) were analyzed by using charge densities from the transferable aspherical-atom University at Buffalo Databank (UBDB). Moreover, we analyzed the electrostatic interaction energy for an ensemble of structures, using molecular dynamic simulations to highlight the main features of electrostatic interactions important for binding affinity

Protonated nucleobases are not fully ionized and may form stable base pairs in the crystalline state

The following paper presents experimental charge density studies of cytosinium chloride, adeninium chloride hemihydrate, and guanine dichloride crystals based on ultra-high resolution X-ray diffraction data and extensive theoretical calculations. Results confirm that the cohesive energies of the studied systems are dominated by contributions from intermolecular electrostatic interactions, as expected for ionic crystals. Electrostatic interactions energies (Ees) usually constitute 95% of total interaction energies. The Ees energies were several times larger in absolute value when compared, for example, to pairs of neutral nucleobases. However, they were not as big as some of the theoretical calculations predicted. This was because the molecules appeared not to be fully ionized in the studied crystals. Apart from chlorine to protonated nucleobase charge transfer, small but visible, charge redistribution within nucleobase cations was observed. Some pairs of single protonated bases in the studied crystals exhibited attractive interactions (negative values of Ees) or unusually low repulsion despite identical molecular charges. This was because strong hydrogen bonding between bases overcompensated overall cation-cation repulsion, the latter being weakened due to charge transfer and molecular charge density polarization

Protonated nucleobases are not fully ionized in their chloride salt crystals and form metastable base pairs further stabilized by the surrounding anions

This paper presents experimental charge-density studies of cytosinium chloride, adeninium chloride hemihydrate and guaninium dichloride crystals based on ultra-high-resolution X-ray diffraction data and extensive theoretical calculations. The results confirm that the cohesive energies of the studied systems are dominated by contributions from intermolecular electrostatic interactions, as expected for ionic crystals. Electrostatic interaction energies (Ees) usually constitute 95% of the total interaction energy. The Ees energies in this study were several times larger in absolute value when compared, for example, with dimers of neutral nucleobases. However, they were not as large as some theoretical calculations have predicted. This was because the molecules appeared not to be fully ionized in the studied crystals. Apart from charge transfer from chlorine to the protonated nucleobases, small but visible charge redistribution within the nucleobase cations was observed. Some dimers of singly protonated bases in the studied crystals, namely a cytosinium–cytosinium trans sugar/sugar edge pair and an adeninium–adeninium trans Hoogsteen/Hoogsteen edge pair, exhibited attractive interactions (negative values of Ees) or unusually low repulsion despite identical molecular charges. The pairs are metastable as a result of strong hydrogen bonding between bases which overcompensates the overall cation–cation repulsion, the latter being weakened due to charge transfer and molecular charge-density polarization

Protonated nucleobases are not fully ionized and may form stable base pairs in the crystalline state

The following paper presents experimental charge density studies of cytosinium chloride, adeninium chloride hemihydrate, and guanine dichloride crystals based on ultra-high resolution X-ray diffraction data and extensive theoretical calculations. Results confirm that the cohesive energies of the studied systems are dominated by contributions from intermolecular electrostatic interactions, as expected for ionic crystals. Electrostatic interactions energies (Ees) usually constitute 95% of total interaction energies. The Ees energies were several times larger in absolute value when compared, for example, to pairs of neutral nucleobases. However, they were not as big as some of the theoretical calculations predicted. This was because the molecules appeared not to be fully ionized in the studied crystals. Apart from chlorine to protonated nucleobase charge transfer, small but visible, charge redistribution within nucleobase cations was observed. Some pairs of single protonated bases in the studied crystals exhibited attractive interactions (negative values of Ees) or unusually low repulsion despite identical molecular charges. This was because strong hydrogen bonding between bases overcompensated overall cation-cation repulsion, the latter being weakened due to charge transfer and molecular charge density polarization

New refinement strategies for pseudoatom databank - towards wider range of application

Pseudoatom databanks, collecting parameters of multipole model of electron densities for various atom types, are used to replace Independent Atom Model by the more accurate Transferable Aspherical Atom Model (TAAM) in crystal structure refinement. They may also be used to reconstruct electron density of a molecule, crystal or biomacromolecular complex in fast yet quite accurate way and compute from it various properties, like energy of electrostatic interactions, for example. Even faster, but similarly accurate in electrostatic energy estimations model exists, the aug-PROmol. Model analogous to aug-PROmol cannot be built from the current pseudoatom databanks, as they perform badly when truncated to the monopole level. Here we searched for new strategies of multipole model refinements, leading to better parametrization already at the monopole level. This would allow to create in a single route of model parametrization a pseudoatom databank, which would be suitable for both crystal structure refinement and rapid electrostatic energy calculations. Such a route does not exist yet, because as we show here, the aug-PROmol model, alternative to the current pseudoatom databanks, is not suitable for crystal X-ray structure refinement. Here we show that cumulative approach to multipole model refinements, as oppose to simultaneous or iterative refinements of all multipole model parameters (Pv, κ, Plm, κ\u27) leads to substantially different models of electron density. Cumulative refinement of Plm first and then κ\u27 parameters is much worse than simultaneous. It results in electron density model giving wrong estimates of electrostatic interaction energies and atomic displacement parameters. Cumulative refinement of two blocks of parameters, Pv and κ first and then Plm and κ\u27, on the other hand, leads to the Pv|Plm’ model having promising properties. It is similarly good as University at Buffalo DataBank (UBDB) of pseudoatoms in X-ray structure TAAM refinement and electrostatic energy estimations, especially for less polar molecules. When truncated to monopole level, the Pv model has a chance to replace the aug-PROmol in fast yet accurate electrostatics energy calculations, although some improvements in κ parametrization for polar functional groups are still needed. The Pv|Plm’ model is also a source of point charges which behave similarly to the RESP charges in electrostatic interaction energy estimations

DiSCaMB: a software library for aspherical atom model X-ray scattering factor calculations with CPUs and GPUs.

It has been recently established that the accuracy of structural parameters from X-ray refinement of crystal structures can be improved by using a bank of aspherical pseudoatoms instead of the classical spherical model of atomic form factors. This comes, however, at the cost of increased complexity of the underlying calculations. In order to facilitate the adoption of this more advanced electron density model by the broader community of crystallographers, a new software implementation called DiSCaMB, 'densities in structural chemistry and molecular biology', has been developed. It addresses the challenge of providing for high performance on modern computing architectures. With parallelization options for both multi-core processors and graphics processing units (using CUDA), the library features calculation of X-ray scattering factors and their derivatives with respect to structural parameters, gives access to intermediate steps of the scattering factor calculations (thus allowing for experimentation with modifications of the underlying electron density model), and provides tools for basic structural crystallographic operations. Permissively (MIT) licensed, DiSCaMB is an open-source C++ library that can be embedded in both academic and commercial tools for X-ray structure refinement

DiSCaMB: a software library for aspherical atom model X-ray scattering factor calculations with CPUs and GPUs.

It has been recently established that the accuracy of structural parameters from X-ray refinement of crystal structures can be improved by using a bank of aspherical pseudoatoms instead of the classical spherical model of atomic form factors. This comes, however, at the cost of increased complexity of the underlying calculations. In order to facilitate the adoption of this more advanced electron density model by the broader community of crystallographers, a new software implementation called DiSCaMB, 'densities in structural chemistry and molecular biology', has been developed. It addresses the challenge of providing for high performance on modern computing architectures. With parallelization options for both multi-core processors and graphics processing units (using CUDA), the library features calculation of X-ray scattering factors and their derivatives with respect to structural parameters, gives access to intermediate steps of the scattering factor calculations (thus allowing for experimentation with modifications of the underlying electron density model), and provides tools for basic structural crystallographic operations. Permissively (MIT) licensed, DiSCaMB is an open-source C++ library that can be embedded in both academic and commercial tools for X-ray structure refinement