Solution dynamics of agostic interactions in T-shaped Pt(II) complexes from ab initio molecular dynamics simulations

Dalton Transactions
Transition metal complexes forming agostic interactions have been extensively surveyed. However, the dynamic behaviour of these interactions is less documented though it could be crucial in chemical processes. For this purpose, ab initio molecular dynamics simulations (AIMD) of some representative T-shaped Pt(II) complexes (quantum mechanics) have been performed in an explicit dichloromethane solvent (molecular mechanics). The dynamics of the agostic interaction in solution strongly depends on the complex, going from stiff to flexible on–off agostic interactions at the time scale of the simulations (about 15 ps). Such behaviour can only be observed by using AIMD methods in solution.Read more

Water Network Perturbation in Ligand Binding: Adenosine A2A Antagonists as a Case Study

Journal of Chemical Information and Modeling
Recent efforts in the computational evaluation of the thermodynamic properties of water molecules have resulted in the development of promising new in silico methods to evaluate the role of water in ligand binding. These methods include WaterMap, SZMAP, GRID/CRY probe, and Grand Canonical Monte Carlo simulations. They allow the prediction of the position and relative free energy of the water molecule in the protein active site and the analysis of the perturbation of an explicit water network (WNP) as a consequence of ligand binding. We have for the first time extended these approaches toward the prediction of kinetics for small molecules and of relative free energy of binding with a focus on the perturbation of the water network and application to large diverse data sets. Our results support a qualitative correlation between the residence time of 12 related triazine adenosine A2A receptor antagonists and the number and position of high energy trapped solvent molecules. From...  Read more

Concerted Hydrogen Atom and Electron Transfer Mechanism for Catalysis by Lysine-Specific Demethylase

The Journal of Physical Chemistry B
We calculate the free energy profile for the postulated hydride transfer reaction mechanism for the catalysis of lysine demethylation by lysine-specific demethylase LSD1. The potential energy surface is obtained by using combined electrostatically embedded multiconfiguration molecular mechanics (EE-MCMM) and single-configuration molecular mechanics (MM). We employ a constant valence bond coupling term to obtain analytical energies and gradients of the EE-MCMM subsystem, which contains 45 quantum mechanics (QM) atoms and which is parametrized with density functional calculations employing specific reaction parameters obtained by matching high-level wave function calculations. In the MM region, we employ the Amber ff03 and TIP3P force fields. The free energy of activation at 300 K is calculated by molecular dynamics (MD) umbrella sampling on a system with 102 090 atoms as the maximum of the free energy profile along the reaction coordinate as obtained by the weighted histogram...  Read more

Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: a QM/MM study

MedChemComm
We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin's ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis.Read more

Photodynamics of Lys+-Trp protein motifs: Hydrogen bonds ensure photostability

Faraday Discussions
Cation-π interactions such as Lys+-Trp, are highly abundant structural motifs in proteins. Both, experimental and theoretical studies of small prototypical gas phase systems, H+Trp, H+Trp·(H2O)n and H+Gly-Trp, indicate such an arrangement as potential hot spot for photodamage and photoinstability. Here, we study the photodynamical properties of a Lys+-Trp pair in the protein human serum albumin (HSA) using nonadiabatic mixed time-dependent density functional theory / molecular mechanics simulations (TDDFT/MM). These simulations show that the findings for small protonated Trp complexes are largely transferable to a more complex protein environment. Under partially hydrated (“dry” conditions), when the –NH3+ head group is not fully solvated,...  Read more