Mauricio Cafiero

Examination of tyrosine/adenine stacking interactions in protein complexes.

The π-stacking interactions between tyrosine amino acid side chains and adenine-bearing ligands are examined. Crystalline protein structures from the protein data bank (PDB) exhibiting face-to-face tyrosine/adenine arrangements were used to construct 20 unique 4-methylphenol/N9-methyladenine (p-cresol/9MeA) model systems. Full geometry optimization of the 20 crystal structures with the M06-2X density functional theory method identified 11 unique low-energy conformations. CCSD(T) complete basis set (CBS) limit interaction energies were estimated for all of the structures to determine the magnitude of the interaction between the two ring systems. CCSD(T) computations with double-ζ basis sets (e.g., 6-31G*(0.25) and aug-cc-pVDZ) indicate that the MP2 method overbinds by as much as 3.07 kcal mol(-1) for the crystal structures and 3.90 kcal mol(-1) for the optimized structures. In the 20 crystal structures, the estimated CCSD(T) CBS limit interaction energy ranges from -4.00 to -6.83 kcal mol(-1), with an average interaction energy of -5.47 kcal mol(-1), values remarkably similar to the corresponding data for phenylalanine/adenine stacking interactions. Geometry optimization significantly increases the interaction energies of the p-cresol/9MeA model systems. The average estimated CCSD(T) CBS limit interaction energy of the 11 optimized structures is 3.23 kcal mol(-1) larger than that for the 20 crystal structures.

Non-Born-Oppenheimer molecular structure and one-particle densities for H2D+

We show that the nonadiabatic (non-Born-Oppenheimer) ground state of a three-nuclei system can be effectively calculated with the use of an explicitly correlated Gaussian basis set with floating centers. Sample calculations performed for the H2D+ system with various basis set sizes show good convergence with respect to both the total energy and the expectation values of the internuclear distances (molecular geometry), the distances between the nuclei and the electrons, and between the electrons. We also provide a derivation of the formulas for one-particle density calculations and some density plots showing the spatial distribution of the H2D+ nuclear and electronic densities.

Chapter 7 - Using Density Functional Theory Methods for Modeling Induction and Dispersion Interactions in Ligand–Protein Complexes

Abstract Density functional theory (DFT) is a relatively fast and inexpensive ab initio computational method that can be used to compute high-accuracy electronic and structural properties of molecular systems. Due to DFT’s formal and algorithmic flexibility, it has the potential to model much larger systems than any other ab initio method. One of the modern challenges in science, particularly computational science, is the accurate modeling of proteins and nucleic acids, and the interactions of these macromolecules with their small molecule substrates, including drugs. These intermolecular interactions include hydrogen bonding and other pure electrostatic interactions, which can be modeled accurately using a wide variety of computational methods, and induction/dispersion interactions, which are more difficult to model with current methods. DFT is the most promising method available today to model full-scale protein–ligand interactions including induction/dispersion. Currently, DFT has been applied to small models that represent these biological systems, and is increasingly being applied to small subsets of these biological systems. These applications provide proof of concept for the potential future application of these methods to full-scale protein–ligand interactions.

Catechol reactivity: Synthesis of dopamine derivatives substituted at the 6-position

ABSTRACT Dopamine is a ubiquitous neurotransmitter essential in the proper functioning of the human body. In addition to this critical role, the catecholamine core has shown utility as a scaffold for numerous drugs and in other applications, like metal detection and adhesive materials. Substituents at the 6-position of dopamine’s catechol core can modulate its stereoelectronic properties, the acidity of its phenolic hydroxyl groups, and the overall hydrophobicity of the molecule. Herein, we report the synthesis of a series of four novel dopamine analogues substituted at the 6-position of catechol core. The 1H NMR chemical shift of the aromatic proton meta to the substituent correlated strongly with the Hammett σm constant, confirming the electronic properties of substituents. GRAPHICAL ABSTRACT

Using simple molecular orbital calculations to predict disease: fast DFT methods applied to enzymes implicated in PKU, Parkinson's disease and Obsessive Compulsive Disorder

Many diseases can be traced to point mutations in the DNA coding for specific enzymes. These point mutations result in the change of one amino acid residue in the enzyme. We have developed a model using simple molecular orbital calculations which can be used to quantitatively determine the change in interaction between the enzymes active site and necessary ligands upon mutation. We have applied this model to three hydroxylase proteins: phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, and we have obtained excellent correlation between our results and observed disease symptoms. Furthermore, we are able to use this agreement as a baseline to screen other mutations which may also cause onset of disease symptoms. Our focus is on systems where the binding is due largely to dispersion, which is much more difficult to model inexpensively than pure electrostatic interactions. Our calculations are run in parallel on a sixteen processor cluster of 64‐bit Athlon processors.