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

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

On the Relationship Between Hydrogen-Bonding Motifs and the 1b1 Splitting in the X-ray Emission Spectrum of Liquid Water

The split of the 1b1 peak observed in the X-ray emission (XE) spectrum of liquid water has been the focus of intense research over the last two decades. Although several hypotheses have been proposed to explain the origin of the 1b1 splitting, a general consensus has not yet been reached. In this study, we introduce a novel theoretical/computational approach which, combining path-integral molecular dynamics (PIMD) simulations carried out with the MB-pol potential energy function and time-dependent density functional theory (TD-DFT) calculations, correctly predicts the split of the 1b1 peak in liquid water and not in crystalline ice. A systematic analysis in terms of the underlying local structure of liquid water at ambient conditions indicates that several different hydrogen-bonding motifs contribute to the overall XE lineshape in the energy range corresponding to emissions from the 1b1 orbitals, which suggests that it is not possible to unambiguously attribute the split of the 1b1 peak to only two specific structural arrangements of the underlying hydrogen-bonding network

Open-Source Multi-GPU-Accelerated QM/MM Simulations with AMBER and QUICK

The quantum mechanics/molecular mechanics (QM/MM) approach is an essential and well-established tool in computational chemistry that has been widely applied in a myriad of biomolecular problems in the literature. In this publication, we report the integration of the QUantum Interaction Computational Kernel (QUICK) program as an engine to perform electronic structure calculations in QM/MM simulations with AMBER. This integration is available through either a file-based interface (FBI) or an application programming interface (API). Since QUICK is an open-source GPU-accelerated code with multi-GPU parallelization, users can take advantage of “free of charge” GPU-acceleration in their QM/MM simulations. In this work, we discuss implementation details and give usage examples. We also investigate energy conservation in typical QM/MM simulations performed at the microcanonical ensemble. Finally, benchmark results for two representative systems, the N-methylacetamide (NMA) molecule and the photoactive yellow protein (PYP) in bulk water, show the performance of QM/MM simulations with QUICK and AMBER using a varying number of CPU cores and GPUs. Our results highlight the acceleration obtained from a single or multiple GPUs; we observed speedups of up to 38x between a single GPU vs. a single CPU core and of up to 2.6x when comparing four GPUs to a single GPU. Results also reveal speedups of up to 3.5x when the API is used instead of FBI.</div

Data for Molecular Dynamics Simulations of Escherichia Coli Cytochrome Bd Oxidase with the Amber Force Field

Cytochrome bd -type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since bd oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing bd oxidases include the Mycobacterium tuberculosis (Mtb) bacterium that causes tuberculosis (TB) in humans, the Vibrio cholerae bacterium that causes cholera, the Pseudomonas aeruginosa bacterium that contributes to antibiotic resistance and sepsis, and the Campylobacter jejuni bacterium that causes food poisoning. Escherichia coli (E. coli) is another organism exhibiting the cytochrome bd oxidase. Since it has the highest sequence identity to Mtb (36 %) and we are ultimately interested in finding drug targets for TB, we have built parameters for the E. coli bd oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome bd -type oxidases (heme b 558 , heme b 595 , and heme d) along with their axial ligands. This data report includes the parameter files that can be used with Amber's LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions

Data for Molecular Dynamics Simulations of Escherichia Coli Cytochrome Bd Oxidase with the Amber Force Field

Cytochrome bd-type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since bd oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing bd oxidases include the Mycobacterium tuberculosis (Mtb) bacterium that causes tuberculosis (TB) in humans, the Vibrio cholerae bacterium that causes cholera, the Pseudomonas aeruginosa bacterium that contributes to antibiotic resistance and sepsis, and the Campylobacter jejuni bacterium that causes food poisoning. Escherichia coli (E. coli) is another organism exhibiting the cytochrome bd oxidase. Since it has the highest sequence identity to Mtb (36 %) and we are ultimately interested in finding drug targets for TB, we have built parameters for the E. coli bd oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome bd-type oxidases (heme b558, heme b595, and heme d) along with their axial ligands. This data report includes the parameter files that can be used with Amber\u27s LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions. </div

Highly Accurate Many-Body Potentials for Simulations of N2O5 in Water: Benchmarks, Development, and Validation

Dinitrogen pentoxide (N2O5) is an important intermediate in the atmospheric chemistry of nitrogen oxides. Although there has been much research, the processes that govern the physical interactions between N2O5 and water are still not fully understood at a molecular level. Gaining quantitative insight from computer simulations requires going beyond the accuracy of classical force fields, while accessing length scales and time scales that are out of reach for high-level quantum chemical approaches. To this end we present the development of MB-nrg many-body potential energy functions for simulations of N2O5 in water. This MB-nrg model is based on electronic structure calculations at the coupled cluster level of theory and is compatible with the successful MB-pol model for water. It provides a physically correct description of long-range many-body interactions in combination with an explicit representation of up to three-body short-range interactions in terms of multidimensional permutationally invariant polynomials. In order to further investigate the importance of the underlying interactions in the model, a TTM-nrg model was also devised. TTM- nrg is a more simplistic representation that contains only two-body short-range interactions represented through Born-Mayer functions. In this work an active learning approach was employed to efficiently build representative training sets of monomer, dimer and trimer structures, and benchmarks are presented to determine the accuracy of our new models in comparison to a range of density functional theory methods. By assessing binding curves, distortion energies of N2O5, and interaction energies in clusters of N2O5 and water, we evaluate the importance of two-body and three-body short-range potentials. The results demonstrate that our MB-nrg model has high accuracy with respect to the coupled cluster reference, outperforms current density functional theory models, and thus enables highly accurate simulations of N2O5 in aqueous environments.</div

Insights Into the Uptake of N2O5 by Aqueous Aerosol Using Chemically Accurate Many-Body Potentials

We study the uptake of N2O5 into pure water using molecular dynamics simulations performed with a recently developed, data driven MB-nrg model. Our model follows the same basis of the MB-pol water many body model and has coupled-cluster accuracy. We quantify the thermodynamics of solvation and adsorption using enhanced sampling techniques and free energy calculations. The free energy profile obtained highlights that N2O5 is selectively adsorbed to the liquid-vapor interface and weakly solvated. We further find that accommodation into the bulk solution occurs rather slowly, and competes with evaporation upon initial adsorption from the gas phase. The rates of each of these processes are evaluated using the free energy barriers and kinetically obtained fluxes. Leveraging the quantitative accuracy of the model, we parameterize and numerically solve a reaction-diffusion equation to determine a likely range of hydrolysis rates consistent with the experimentally observed reactive uptake coefficient in pure water. The physical and chemical parameters deduced here, including the solubility, accommodation coefficient, and hydrolysis rate, afford a foundation for which to consider the reactive loss of N2O5 in more complex solutions

Harnessing the Power of Multi-GPU Acceleration into the Quantum Interaction Computational Kernel Program

We report a new multi-GPU capable ab initio Hartree-Fock/density functional theory implementation integrated into the open source QUantum Interaction Computational Kernel (QUICK) program. Details on the load balancing algorithms for electron repulsion integrals and exchange correlation quadrature across multiple GPUs are described. Benchmarking studies carried out on up to 4 GPU nodes, each containing 4 NVIDIA V100-SMX2 type GPUs demonstrate that our implementation is capable of achiev- ing excellent load balancing and high parallel efficiency. For representative medium to large size protein/organic molecular sys- tems, the observed efficiencies remained above 86%. The accelerations on NVIDIA A100, P100 and K80 platforms also have real- ized parallel efficiencies higher than 74%, paving the way for large-scale ab initio electronic structure calculations.</div

Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity

International audienceCarbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors