Solvent Effects and pH Dependence of the X-ray Absorption Spectra of Proline from Electrostatic Embedding Quantum Mechanics/Molecular Mechanics and Mixed-Reference Spin-Flip Time-dependent Density-Functional Theory.

The accurate description of solvent effects on X-ray absorption spectra (XAS) is fundamental for comparing the simulated spectra with experiments in solution. Currently, few protocols exist that can efficiently reproduce the effects of the solute/solvent interactions on XAS. Here, we develop an efficient and accurate theoretical protocol for simulating the solvent effects on XAS. The protocol combines electrostatic embedding QM/MM based on electrostatic potential fitted operators for describing the solute/solvent interactions and mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT) for simulating accurate XAS spectra. To demonstrate the capabilities of our protocol, we compute the X-ray absorption of neutral proline in the gas phase and ionic proline in water in all relevant K-edges, showing excellent agreement with experiments. We show that states represented by core to π* transitions are almost unaffected by the interaction with water, whereas the core to σ* transitions are more impacted by the fluctuation of proline structure and the electrostatic interaction with the solvent. Finally, we reconstruct the pH-dependent XAS of proline in solution, determining that the N K-edge can be used to distinguish its three protonation states.

An efficient electrostatic embedding QM/MM method using periodic boundary conditions based on particle-mesh Ewald sums and electrostatic potential fitted charge operators.

Hybrid quantum mechanics/molecular mechanics (QM/MM) models are successful at describing the properties and reactivity of biological macromolecules. Combining ab initio QM/MM methods and periodic boundary conditions (PBC) is currently the optimal approach for modeling chemical processes in an infinite environment, but frequently, these models are too time-consuming for general applicability to biological systems in a solution. Here, we define a simple and efficient electrostatic embedding QM/MM model in PBC, combining the benefits of electrostatic potential fitted atomic charges and particle-mesh Ewald sums, which can efficiently treat systems of an arbitrary size at a reasonable computational cost. To illustrate this, we apply our scheme to extract the lowest singlet excitation energies from a model for Arabidopsis thaliana cryptochrome 1 containing circa 93 000 atoms, accurately reproducing the experimental absorption maximum.

Analytic Gradients for the Electrostatic Embedding QM/MM Model in Periodic Boundary Conditions Using Particle-Mesh Ewald Sums and Electrostatic Potential Fitted Charge Operators.

Long-range electrostatic effects are fundamental for describing chemical reactivity in the condensed phase. Here, we present the methodology of an efficient quantum mechanical/molecular mechanical (QM/MM) model in periodic boundary conditions (PBC) compatible with QM/MM boundaries at chemical bonds. The method combines electrostatic potential fitted charge operators and electrostatic potentials derived from the smooth particle-mesh Ewald (PME) sum approach. The total energy and its analytic first derivatives with respect to QM, MM, and lattice vectors allow QM/MM molecular dynamics (MD) in the most common thermodynamic ensembles. We demonstrate the robustness of the method by performing a QM/MM MD equilibration of methanol in water. We simulate the cis/trans isomerization free-energy profiles in water of proline amino acid and a proline-containing oligopeptide, showing a correct description of the reaction barrier. Our PBC-compatible QM/MM model can efficiently be used to study the chemical reactivity in the condensed phase and enzymatic catalysis.