Interaction at a distance: Xenon migration in Mb.

The transport of ligands, such as NO or O2, through internal cavities is essential for the function of globular proteins, including hemoglobin, myoglobin (Mb), neuroglobin, truncated hemoglobins, or cytoglobin. For Mb, several internal cavities (Xe1 through Xe4) were observed experimentally and they were linked to ligand storage. The present work determines barriers for xenon diffusion and relative stabilization energies for the ligand in the initial and final pocket, linking a transition depending on the occupancy state of the remaining pockets from both biased and unbiased molecular dynamics simulations. It is found that the energetics of a particular ligand migration pathway may depend on the direction in which the transition is followed and the occupancy state of the other cavities. Furthermore, the barrier height for a particular transition can depend in a non-additive fashion on the occupancy of either cavity A or B or simultaneous population of both cavities, A and B. Multiple repeats for the Xe1 → Xe2 transition reveal that the activation barrier is a distribution of barrier heights rather than one single value, which is confirmed by a distribution of transition times for the same transition from unbiased simulations. Dynamic cross correlation maps demonstrate that correlated motions occur between adjacent residues or through space, residue Phe138 is found to be a gate for the Xe1 → Xe2 transition, and the volumes of the internal cavities vary along the diffusion pathway, indicating that there is dynamic communication between the ligand and the protein. These findings suggest that Mb is an allosteric protein.

Local Hydration Control and Functional Implications Through S-Nitrosylation of Proteins: Kirsten Rat Sarcoma Virus (K-RAS) and Hemoglobin (Hb).

S-nitrosylation, the covalent addition of NO to the thiol side chain of cysteine, is an important post-transitional modification (PTM) that can affect the function of proteins. As such, PTMs extend and diversify protein function and thus characterizing consequences of PTM at a molecular level is of great interest. Although PTMs can be detected through various direct/indirect methods, they lack the capability to investigate the modifications with molecular detail. In the present work local and global structural dynamics, their correlation, the hydration structure, and the infrared spectroscopy for WT and S-nitrosylated Kirsten rat sarcoma virus (K-RAS) and hemoglobin (Hb) are characterized from molecular dynamics simulations. It is found that attaching NO to Cys118 in K-RAS rigidifies the protein in the Switch-I region which has functional implications, whereas for Hb, nitrosylation at Cys93 at the ß1 chain increases the flexibility of secondary structural motives for Hb in its T0 and R4 conformational substates. Solvent water access decreased by 40% after nitrosylation in K-RAS, similar to Hb for which, however, local hydration of the R4SNO state is yet lower than for T0SNO. Finally, S-nitrosylation leads to detectable peaks for the NO stretch frequency, but the congested IR spectral region will make experimental detection of these bands difficult. Overall, S-nitrosylation in these two proteins is found to influence hydration, protein flexibility, and conformational dynamics which are all eventually involved in protein regulation and function at a molecular level.

Solvent Effects on the Menshutkin Reaction.

The Menshutkin reaction is a methyl transfer reaction relevant in fields ranging from biochemistry to chemical synthesis. In the present work, the energetics and solvent distributions for NH3+MeCl and Pyr+MeBr reactions were investigated in explicit solvent (water, methanol, acetonitrile, benzene, cyclohexane) by means of reactive molecular dynamics simulations. For polar solvents (water, methanol, and acetonitrile) and benzene, strong to moderate catalytic effects for both reactions were found, whereas apolar and bulky cyclohexane interacts weakly with the solute and does not show pronounced barrier reduction. The calculated barrier heights for the Pyr+MeBr reaction in acetonitrile and cyclohexane are 23.2 and 28.1 kcal/mol compared with experimentally measured barriers of 22.5 and 27.6 kcal/mol, respectively. The solvent distributions change considerably between reactant and TS but comparatively little between TS and product conformations of the solute. As the system approaches the transition state, correlated solvent motions occur which destabilize the solvent-solvent interactions. This is required for the system to surmount the barrier. Finally, it is found that the average solvent-solvent interaction energies in the reactant, TS, and product state geometries are correlated with changes in the solvent structure around the solute.

Spectroscopy, Dynamics, and Hydration of S-Nitrosylated Myoglobin.

S-Nitrosylation, the covalent addition of NO to the thiol side chain of cysteine, is an important post-transitional modification that can alter the function of various proteins. The structural dynamics and vibrational spectroscopy of S-nitrosylation in the condensed phase are investigated for the methyl-capped cysteine model system and for myoglobin. Using conventional point charge and physically more realistic multipolar force fields for the -SNO group, it is found that the SN- and NO-stretch and the SNO-bend vibrations can be located and distinguished from the other protein modes for simulations of MbSNO at 50 K. The finding of stable cis- and trans-MbSNO agrees with experimental findings on other proteins as is the observation of buried -SNO. For MbSNO the observed relocation of the EF loop in the simulations by ∼3 Šis consistent with the available X-ray structure, and the conformations adopted by the -SNO label are in good overall agreement with the X-ray structure. Despite the larger size of the -SNO group compared with -SH, MbSNO recruits more water molecules in the first two hydration shells due to stronger electrostatic interactions. Similarly, when comparing the hydration between the A- and H-helices, they differ by up to 30% between WT and MbSNO. This suggests that local hydration can also be significantly modulated through nitrosylation.

Computational Study of Photo-oxidative Degradation Mechanisms of Boron-Containing Oligothiophenes.

We have modeled possible photo-oxidative degradation pathways for a set of boron-containing oligothiophenes, which have potential use in organic electronic devices. Photogenerated reactive oxygen species such as hydroxyl radical, hydroperoxyl radical, and singlet and triplet molecular oxygen are taken into account in three main pathways, namely, sulfoxide formation, sequential addition, and stepwise singlet molecular oxygen addition. Density functional theory at the B3LYP level is used to assess the reaction kinetics and thermodynamics. Our findings show that the influence of the number of thiophene rings and the presence of boron is in most cases minor in terms of degradation. The formation of sulfoxide on the thiophene ring is among the easiest degradation pathways if hydroxyl radical is present in the system. The hydroxyl radical attack on the Cß of thiophene ring of BMBE-1T (2,5-bis(E-dimesitylborylethenyl)thiophene) forms the BMBE-1T(C)OH radical adduct which is kinetically and thermodynamically more favorable than the hydroperoxyl radical attack. The stepwise triplet molecular oxygen addition on the BMBE-1T(C)OH radical adduct has a free energy barrier around 19 kcal·mol-1, and it results in thermodynamically stable degradation product via ring cleavage. Stepwise reactions with singlet molecular oxygen have energy barriers of roughly 40 kcal·mol-1. Singlet molecular oxygen attack on the α-carbon of the thiophene ring is kinetically much more favored than the attack on the beta carbon. Our results elucidate the preferred degradation mechanism of the thiophene backbone of the selected photoactive oligomers. Moreover, the findings of this theoretical study clarify the photostability, and hence the potential drawbacks, of the large-scale use of this class of polythiophenes.

Design of donor-acceptor copolymers for organic photovoltaic materials: a computational study.

80 different push-pull type organic chromophores which possess Donor-Acceptor (D-A) and Donor-Thiophene-Acceptor-Thiophene (D-T-A-T) structures have been systematically investigated by means of density functional theory (DFT) and time-dependent DFT (TD-DFT) at the B3LYP/6-311G* level. The introduction of thiophene (T) in the chain has allowed us to monitor the effect of π-spacers. Benchmark studies on the methodology have been carried out to predict the HOMO and LUMO energies and optical band gaps of the D-A systems accurately. The HOMO and LUMO energies and transition dipoles are seen to converge for tetrameric oligomers, and the latter have been used as optimal chain length to evaluate various geometrical and optoelectronic properties such as bond length alternations, distortion energies, frontier molecular orbital energies, reorganization energies and excited-state vertical transition of the oligomers. Careful analysis of our findings has allowed us to propose potential donor-acceptor couples to be used in organic photovoltaic cells.