Aravindhan Ganesan

Intramolecular interactions of L-phenylalanine revealed by inner shell chemical shift

Intramolecular interactions of the functional groups, carboxylic acid, amino, and phenyl in L-phenylalanine have been revealed through inner shell chemical shift. The chemical shift and electronic structures are studied using its derivatives, 2-phenethylamine (PEA) and 3-phenylpropionic acid (PPA), through substitutions of the functional groups on the chiral carbon C(alpha), i.e., carboxylic acid (-COOH) and amino (-NH(2)) groups. Inner shell ionization spectra of L-phenylalanine are simulated using density functional theory based B3LYP/TZVP and LB94/et-pVQZ models, which achieve excellent agreement with the most recently available synchrotron sourced x-ray photoemission spectroscopy of L-phenylalanine (Elettra, Italy). The present study reveals insight into behavior of the peptide bond (CO-NH) through chemical shift of the C(1)-C(alpha)-C(beta)(-C(gamma)) chain and intramolecular interactions with phenyl. It is found that the chemical shift of the carbonyl C(1)(=O) site exhibits an apparently redshift (smaller energy) when interacting with the phenyl aromatic group. Removal of the amino group (-NH(2)) from L-phenylalanine (which forms PPA) brings this energy on C(1) close to that in L-alanine (delta<0.01 eV). Chemical environment of C(alpha) and C(beta) exhibits more significant differences in L-alanine than in the aromatic species, indicating that the phenyl group indeed affects the peptide bond in the amino acid fragment. No direct evidences are found that the carbonyl acid and amino group interact with the phenyl ring through conventional hydrogen bonds.

Intramolecular interactions of L-phenylalanine: Valence ionization spectra and orbital momentum distributions of its fragment molecules.

Intramolecular interactions between fragments of L‐phenylalanine, i.e., phenyl and alaninyl, have been investigated using dual space analysis (DSA) quantum mechanically. Valence space photoelectron spectra (PES), orbital energy topology and correlation diagram, as well as orbital momentum distributions (MDs) of L‐phenylalanine, benzene and L‐alanine are studied using density functional theory methods. While fully resolved experimental PES of L‐phenylalanine is not yet available, our simulated PES reproduces major features of the experimental measurement. For benzene, the simulated orbital MDs for 1e1g and 1a2u orbitals also agree well with those measured using electron momentum spectra. Our theoretical models are then applied to reveal intramolecular interactions of the species on an orbital base, using DSA. Valence orbitals of L‐phenylalanine can be essentially deduced into contributions from its fragments such as phenyl and alaninyl as well as their interactions. The fragment orbitals inherit properties of their parent species in energy and shape (ie., MDs). Phenylalanine orbitals show strong bonding in the energy range of 14‐20 eV, rather than outside of this region. This study presents a competent orbital based fragments‐in‐molecules picture in the valence space, which supports the fragment molecular orbital picture and building block principle in valence space. The optimized structures of the molecules are represented using the recently developed interactive 3D‐PDF technique.

Photoelectron spectra of some antibiotic building blocks: 2-azetidinone and thiazolidine-carboxylic acid.

X-ray photoelectron spectra of the core and valence levels of the fundamental building blocks of β-lactam antibiotics have been investigated and compared with theoretical calculations. The spectra of the compounds 2-azetidinone and the 2- and 4-isomers of thiazolidine-carboxylic acid are interpreted in the light of theoretical calculations. The spectra of the two isomers of thiazolidine-carboxylic acid are rather similar, as expected, but show clear effects due to isomerization. Both isomers are analogues of proline, which is well-known to populate several low energy conformers in the gas phase. We have investigated the low energy conformers of thiazolidine-4-carboxylic acid theoretically in more detail and find some spectroscopic evidence that multiple conformers may be present. The measured valence levels are assigned for all three compounds, and the character of the frontier orbitals is identified and analyzed.

A study of aliphatic amino acids using simulated vibrational circular dichroism and Raman optical activity spectra

Vibrational optical activity (VOA) spectra, such as vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra, of aliphatic amino acids are simulated using density functional theory (DFT) methods in both gas phase (neutral form) and solution (zwitterionic form), together with their respective infrared (IR) and Raman spectra of the amino acids. The DFT models, which are validated by excellent agreements with the available experimental Raman and ROA spectra of alanine in solution, are employed to study other aliphatic amino acids. The inferred (IR) intensive region (below 2000 cm-1) reveals the signature of alkyl side chains, whereas the Raman intensive region (above 3000 cm-1) contains the information of the functional groups in the amino acids. Furthermore, the chiral carbons of the amino acids (except for glycine) dominate the VCD and ROA spectra in the gas phase, but the methyl group vibrations produce stronger VCD and ROA signals in solution. The C-H related asymmetric vibrations dominate the VOA spectra (i.e., VCD and ROA) > 3000 cm-1 reflecting the side chain structures of the amino acids. Finally the carboxyl and the C(2)H modes of aliphatic amino acids, together with the side chain vibrations, are very active in the VCD/IR and ROA/Raman spectra, which makes such the vibrational spectroscopic methods a very attractive means to study biomolecules.

Density functional study of Cu2+-phenylalanine complex under micro-solvation environment

We present an atomistic study carried out using density functional calculations including structural relaxations and Car-Parrinello Molecular Dynamics (CPMD) simulations, aiming to investigate the structures of phenylalanine-copper (II) ([Phe-Cu](2+)) complexes and their micro-solvation processes. The structures of the [Phe-Cu](2+) complex with up to four water molecules are optimized using the B3LYP/6-311++G** model in gas phase to identify the lowest energy structures at each degree of solvation (n=0-4). It is found that the phenylalanine appears to be in the neutral form in isolated and mono-hydrated complexes, but in the zwitterionic form in other hydrated complexes (with n≥2). The most stable structures of the complexes suggest that the Cu(2+)-π interactions are not dominant in the [Phe-Cu](2+) complexes. The present CPMD simulations of the lowest energy micro-hydrated [Phe-Cu](2+) complexes also reveal that the maximum coordination of Cu(2+) in the presence of the Phe ligand does not exceed four: the oxygen atoms from three water molecules and one carboxyl oxygen atom of Phe. Any excess water molecules will migrate to the second solvation shell. Moreover a unique structural motif, (N)H···O(3)···H2O-Cu(2+) is present in the lowest energy complexes, which is recognized to be significant in stabilizing the structures of the complexes. Extensively rich information of the structures, energetics, hydrogen bonds and dynamics of the lowest energy complexes are discussed.

Modeling the human Na v 1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

Effects of protein-protein interactions and ligand binding on the ion permeation in KCNQ1 potassium channel

The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and (ii) the binding of chromanol 293B ligand and its derivatives into the complex. The results reveal that interactions between KCNQ1 with KCNE1 causes a pore constriction in the former, which in-turn forms small energetic barriers in the ion-permeation pathway. These findings correlate with the previous experimental reports that interactions of KCNE1 dramatically slows the activation of KCNQ1. Upon ligand-binding onto the complex, the energy-barriers along ion permeation path are more pronounced, as expected, therefore, requiring higher force in our steered-MD simulations. Nevertheless, pulling the ion when a weak blocker is bound to the channel does not necessitate high force in SMD. This indicates that our SMD simulations have been able to discern between strong and week blockers and reveal their influence on potassium ion permeation. The findings presented here will have some implications in understanding the potential off-target interactions of the drugs with the KCNQ1/KCNE1 channel that lead to cardiotoxic effects.

Fragment based electronic structural analysis of l-phenylalanine using calculated ionization spectroscopy and dual space analysis

Two sets of amino acid-containing fragment schemes, the alanine/benzene scheme and the glycine/toluene scheme, are employed to study the electronic structure of an aromatic amino acid, L-phenylalanine (Phe). The calculated ionization energies (IEs) and the theoretical momentum distributions (TMDs) of the valence orbitals for the related molecules are analyzed to reveal the intra-molecular interactions through the fragments-in-molecules scheme. Density functional theory (DFT) based and Green function based quantum mechanical calculations as well as available experimental measurements are used in this study. It is found that the strong chemical bonding character of Phe seems to appear in the middle valence region of 11–20 eV, which largely shows the dependency of the fragment schemes. The valence energy region of 14 20 eV) and the outermost valence space (i.e. the frontier orbitals) are less affected by the fragment schemes. These observations are confirmed using combined information on the position and momentum spaces in dual space analysis (DSA).

Electronic structure and intramolecular interactions in three methoxyphenol isomers

Electronic structures and intramolecular interactions of three methoxyphenol positional isomers and their rotamers have been studied using core X-ray photoelectron spectroscopy and quantum mechanical calculations. The structural calculations are benchmarked against published calculations of enthalpy of formation and rotational constants, and published experimental data. The good agreement obtained confirms the accuracy of the results. A single rotamer of each isomer was then selected and the C 1s photoelectron spectra calculated and compared with experiment. Good agreement is obtained, and the calculations were extended to investigate the effects of conformation. For 3-methoxyphenol, the difference in the C 1s binding energy of the conformers is small, <0.15 eV. For 2-methoxyphenol, whose ground state includes an OH⋯OCH3 hydrogen bond, the higher energy rotamers show the largest shifts for the methyl carbon atom, whereas the ring carbon bonded to OH hardly shifts The theoretical differences in core level energies of the two rotamers of 4-MP are still smaller, <0.05 eV. By comparing calculations neglecting or including final state relaxation upon ionization, the relaxation energy of the phenyl carbons in all isomers is found to be ∼0.5 eV, while that of the methyl groups is ∼1.3 eV.