Exploring Coupled Redox and pH Processes with a Force Field-Based Approach: Applications to Five Different Systems

Abstract

Coupled redox and pH-driven processes are at the core of many important biological mechanisms. As the distribution of protonation and redox states in a system is associated with the pH and redox potential of the solution, having efficient computational tools that can simulate under these conditions become very important. Such tools have the potential to provide information that complement and drive experiments. In previous publications we have presented the implementation of the constant pH and redox potential molecular dynamics (C(pH,E)MD) method in AMBER and we have shown how multidimensional replica exchange can be used to significantly enhance the convergence efficiency of our simulations. In the current work, after an improvement in our C(pH,E)MD approach that allows a given residue to be simultaneously pH- and redox-active, we have employed our methodologies to study five different systems of interest in the literature. We present results for: capped tyrosine dipeptide, two maquette systems containing one pH- and redox-active tyrosine (α3Y and peptide A), and two proteins that contain multiple heme groups (diheme cytochrome c from Rhodobacter sphaeroides and Desulfovibrio vulgaris Hildenborough cytochrome c3). We show that our results can provide new insights into previous theoretical and experimental findings by using a fully force field-based and GPUaccelerated approach, which allows the simulations to be executed with high computational performance.

Heme Hopping Falls Short: What Explains Anti-Arrhenius Conductivity in a Multi-heme Cytochrome Nanowire?

“…Use of a forcefield specifically parameterized for bis-histidine c -type hemes 98, 99 that has been shown to reasonably estimate E ° within ~0.120 V from electrostatic free energy differences 100, 101 and that accurately describes relative differences in electric fields. 102…”

“…In addition to these methodological refinements, E °s computed with QM/MM@MD were now compared with those from nearly 3.0 μs of constant redox or constant redox and pH molecular dynamics (CE- or C(E,pH)MD) simulations (Table S3). 101, 112 Separately, nearly 1.0 μs of constant pH molecular dynamics (CpHMD) was performed in two different redox microstates (i.e., combinations of oxidized and/or reduced hemes) (Table S2). These classical electrostatics-based techniques revealed the influence of heme-heme and heme-acid/base (redox-Bohr) interactions on the computed E °s (Table S14; Figure S8) and pK a s (Table S29, S30; Figure S11).…”

“…QM/MM@MD differences on E ° were similar in magnitude to differences previously observed between C(E,pH)MD and experimental data on multi-heme proteins. 101…”

“…The C(E,pH)MD vs. QM/MM@MD differences on 𝐸 ∘ were similar in magnitude to differences previously observed between C(E,pH)MD and experimental data on multi-heme proteins. 101 Notwithstanding the reasonable agreement, the C(E,pH)MD and QM/MM@MD computations respectively included and excluded heme-heme and redox-Bohr interactions. 𝐸 ∘ s were obtained with C(E,pH)MD by simultaneously titrating the redox and protonation states of all 18 hemes in an OmcS trimer for a range of solution potentials at pH 7.…”

“…Table S1 gives a detailed comparison of the implementations in the present and prior 83 works. The present work is distinguished by: 1) Use of a forcefield specifically parameterized for bis-histidine c-type hemes 98,99 that has been shown to reasonably estimate 𝐸 ∘ within ~0.120 V from electrostatic free energy differences 100,101 and that accurately describes relative differences in electric fields. 102 2) Propagation of separate simulations at 100 to 400 K in 25 K increments, instead of only 270 and 310 K, to characterize temperature-dependent structural transitions.…”