We investigate the conformation and solvent effect on the conformational change and ionization of amino acids at the molecular level. Amino acids are the building blocks of proteins. This work can be considered as the first step towards understanding intra- and inter-molecular interactions and their roles in determining protein structure, folding, and interactions between proteins and ligands....[ Read more ]

We investigate the conformation and solvent effect on the conformational change and ionization of amino acids at the molecular level. Amino acids are the building blocks of proteins. This work can be considered as the first step towards understanding intra- and inter-molecular interactions and their roles in determining protein structure, folding, and interactions between proteins and ligands.

Accurate calculation of hydrogen bond strength is a great challenge. Traditional ab initio methods can yield satisfactory results, but are computational too expensive to large molecular systems. Density function theory (DFT) offers a promising alternative, but often shows deficiency in dealing with nonbonded interaction. This work starts with a detailed examination on 15 popular DFT methods in treating model systems which simulate the all types of intermolecular HB interactions in related systems, as well as the conformer stability of three representative amino acids. We find that the X3LYP functional has the overall best performance, balance between the accuracy and efficiency, in describing the complicated interactions involving in the systems of interest. This work thus also establishes, by using the G3 method, several benchmark data sets for high quality description of intermolecular hydrogen bonding energies and intramolecular hydrogen bondings, which are useful for future DFT functional development and validation.

All amino acids are polar molecules and greatly influenced by water solvent environment that provides a polarization field. Such long range interactions from bulk solvent water can be well described by using dielectric continuum model. On the other hand, the atomic specific short range interactions from the first solvation shell are also crucial. For example, solvent water molecule can act as either the proton donor or acceptor to form hydrogen bonds with amino acids; it can also be the donor and acceptor at same time in bridging between the carboxylic group and the amino group. Hence, a proper method is needed to treat accurately and efficiently the intramolecular interaction (specially the hydrogen-bond between the carbonyl and amino group) within amino acid molecule, the intermolecular hydrogen-bond interactions between amino acid and water environment, and also the long range polarization effect. This work explores a combined explicit and implicit solvation approach, and exemplifies the method on a representative amino acid, glycine molecule in solution. It treats glycine with a few explicit water molecules (n = 1∼8) for specific hydrogen bonding, plus the polarizable continuum model (PCM) to account for the effect of bulk water. It is found that the polarizable continuum model by nature is incapable of describing the atomic specific interaction between the amino acid and the close contacting water molecule(s). Consequently, the implicit water approach via polarizable continuum model alone cannot describe properly some low-lying conformers. These conformers are however also important to the structures and reactions of amino acids, as they often differ from the global minima within thermal energy. On the other hand, the explicit water treatment alone for all solvent water molecules is impractical and inefficient. This work reveals that for glycine, even with up to eight explicit water molecules, is unable to stabilize the dipolar zwitterionic form as it is in solution. Combined both explicit and implicit water, the zwitterionic form distinguishes itself as the most stable configuration when more than two explicit water molecules are included. This work updates the existing literature for glycine-water complexes, mostly optimized at the restricted Hartree-Fock level in the gas phase, with many new configurations, demonstrating the important role played by the correlation effects and solvation effects on geometries. The present work signifies the combined effects of the relative stability of glycine conformers, the HB strength between glycine and water, and the long range solvent effect of bulk water. The established methodology is applicable to other amino acids and small peptides in solution. The understanding sheds light on the properties of proteins in solution. The detailed results, geometries, HB strengths and the relative conformational energies are valuable for validation and development of force field for protein related simulations.