Amber free energy tools: Interoperable software for free energy simulations using generalized quantum mechanical/molecular mechanical and machine learning potentials.

We report the development and testing of new integrated cyberinfrastructure for performing free energy simulations with generalized hybrid quantum mechanical/molecular mechanical (QM/MM) and machine learning potentials (MLPs) in Amber. The Sander molecular dynamics program has been extended to leverage fast, density-functional tight-binding models implemented in the DFTB+ and xTB packages, and an interface to the DeePMD-kit software enables the use of MLPs. The software is integrated through application program interfaces that circumvent the need to perform "system calls" and enable the incorporation of long-range Ewald electrostatics into the external software's self-consistent field procedure. The infrastructure provides access to QM/MM models that may serve as the foundation for QM/MM-ΔMLP potentials, which supplement the semiempirical QM/MM model with a MLP correction trained to reproduce ab initio QM/MM energies and forces. Efficient optimization of minimum free energy pathways is enabled through a new surface-accelerated finite-temperature string method implemented in the FE-ToolKit package. Furthermore, we interfaced Sander with the i-PI software by implementing the socket communication protocol used in the i-PI client-server model. The new interface with i-PI allows for the treatment of nuclear quantum effects with semiempirical QM/MM-ΔMLP models. The modular interoperable software is demonstrated on proton transfer reactions in guanine-thymine mispairs in a B-form deoxyribonucleic acid helix. The current work represents a considerable advance in the development of modular software for performing free energy simulations of chemical reactions that are important in a wide range of applications.

Molecular Insights into Chemical Reactions at Aqueous Aerosol Interfaces.

Atmospheric aerosols facilitate reactions between ambient gases and dissolved species. Here, we review our efforts to interrogate the uptake of these gases and the mechanisms of their reactions both theoretically and experimentally. We highlight the fascinating behavior of N2O5 in solutions ranging from pure water to complex mixtures, chosen because its aerosol-mediated reactions significantly impact global ozone, hydroxyl, and methane concentrations. As a hydrophobic, weakly soluble, and highly reactive species, N2O5 is a sensitive probe of the chemical and physical properties of aerosol interfaces. We employ contemporary theory to disentangle the fate of N2O5 as it approaches pure and salty water, starting with adsorption and ending with hydrolysis to HNO3, chlorination to ClNO2, or evaporation. Flow reactor and gas-liquid scattering experiments probe even greater complexity as added ions, organic molecules, and surfactants alter the interfacial composition and reaction rates. Together, we reveal a new perspective on multiphase chemistry in the atmosphere. Expected final online publication date for the Annual Review of Physical Chemistry, Volume 75 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Geometry Optimization: A Comparison of Different Open-Source Geometry Optimizers.

Based on a series of energy minimizations with starting structures obtained from the Baker test set of 30 organic molecules, a comparison is made between various open-source geometry optimization codes that are interfaced with the open-source QUantum Interaction Computational Kernel (QUICK) program for gradient and energy calculations. The findings demonstrate how the choice of the coordinate system influences the optimization process to reach an equilibrium structure. With fewer steps, internal coordinates outperform Cartesian coordinates, while the choice of the initial Hessian and Hessian update method in quasi-Newton approaches made by different optimization algorithms also contributes to the rate of convergence. Furthermore, an available open-source machine learning method based on Gaussian process regression (GPR) was evaluated for energy minimizations over surrogate potential energy surfaces with both Cartesian and internal coordinates with internal coordinates outperforming Cartesian. Overall, geomeTRIC and DL-FIND with their default optimization method as well as with the GPR-based model using Hartree-Fock theory with the 6-31G** basis set needed a comparable number of geometry optimization steps to the approach of Baker using a unit matrix as the initial Hessian to reach the optimized geometry. On the other hand, the Berny and Sella offerings in ASE outperformed the other algorithms. Based on this, we recommend using the file-based approaches, ASE/Berny and ASE/Sella, for large-scale optimization efforts, while if using a single executable is preferable, we now distribute QUICK integrated with DL-FIND.

AmberTools.

AmberTools is a free and open-source collection of programs used to set up, run, and analyze molecular simulations. The newer features contained within AmberTools23 are briefly described in this Application note.

Quantum Mechanics/Molecular Mechanics Simulations on NVIDIA and AMD Graphics Processing Units.

We have ported and optimized the graphics processing unit (GPU)-accelerated QUICK and AMBER-based ab initio quantum mechanics/molecular mechanics (QM/MM) implementation on AMD GPUs. This encompasses the entire Fock matrix build and force calculation in QUICK including one-electron integrals, two-electron repulsion integrals, exchange-correlation quadrature, and linear algebra operations. General performance improvements to the QUICK GPU code are also presented. Benchmarks carried out on NVIDIA V100 and AMD MI100 cards display similar performance on both hardware for standalone HF/DFT calculations with QUICK and QM/MM molecular dynamics simulations with QUICK/AMBER. Furthermore, with respect to the QUICK/AMBER release version 21, significant speedups are observed for QM/MM molecular dynamics simulations. This significantly increases the range of scientific problems that can be addressed with open-source QM/MM software on state-of-the-art computer hardware.

Effects of Microhydration on the Mechanisms of Hydrolysis and Cl- Substitution in Reactions of N2 O5 and Seawater.

The reaction of N2 O5 at atmospheric interfaces has recently received considerable attention due to its importance in atmospheric chemistry. N2 O5 reacts preferentially with Cl- to form ClNO2 /NO3 - (Cl- substitution), but can also react with H2 O to form 2HNO3 (hydrolysis). In this paper, we explore these competing reactions in a theoretical study of the clusters N2 O5 /Cl- /nH2 O (n=2-5), resulting in the identification of three reaction motifs. First, we uncovered an SN 2-type Cl- substitution reaction of N2 O5 that occurs very quickly due to low barriers to reaction. Second, we found a low-lying pathway to hydrolysis via a ClNO2 intermediate (two-step hydrolysis). Finally, we found a direct hydrolysis pathway where H2 O attacks N2 O5 (one-step hydrolysis). We find that Cl- substitution is the fastest reaction in every cluster. Between one-step and two-step hydrolysis, we find that one-step hydrolysis barriers are lower, making two-step hydrolysis (via ClNO2 intermediate) likely only when concentrations of Cl- are high.

Reaction pathways, proton transfer, and proton pumping in ba3 class cytochrome c oxidase: perspectives from DFT quantum chemistry and molecular dynamics.

After drawing comparisons between the reaction pathways of cytochrome c oxidase (CcO, Complex 4) and the preceding complex cytochrome bc1 (Complex 3), both being proton pumping complexes along the electron transport chain, we provide an analysis of the reaction pathways in bacterial ba3 class CcO, comparing spectroscopic results and kinetics observations with results from DFT calculations. For an important arc of the catalytic cycle in CcO, we can trace the energy pathways for the chemical protons and show how these pathways drive proton pumping of the vectorial protons. We then explore the proton loading network above the Fe heme a3-CuB catalytic center, showing how protons are loaded in and then released by combining DFT-based reaction energies with molecular dynamics simulations over states of that cycle. We also propose some additional reaction pathways for the chemical and vector protons based on our recent work with spectroscopic support.

Computer-aided drug design, quantum-mechanical methods for biological problems.

Quantum chemistry enables to study systems with chemical accuracy (<1 kcal/mol from experiment) but is restricted to a handful of atoms due to its computational expense. This has led to ongoing interest to optimize and simplify these methods while retaining accuracy. Implementing quantum mechanical (QM) methods on modern hardware such as multiple-GPUs is one example of how the field is optimizing performance. Multiscale approaches like the so-called QM/molecular mechanical method are gaining popularity in drug discovery because they focus the application of QM methods on the region of choice (e.g., the binding site), while using efficient MM models to represent less relevant areas. The creation of simplified QM methods is another example, including the use of machine learning to create ultra-fast and accurate QM models. Herein, we summarize recent advancements in the development of optimized QM methods that enhance our ability to use these methods in computer aided drug discovery.

Uptake of N2O5 by aqueous aerosol unveiled using chemically accurate many-body potentials.

The reactive uptake of N2O5 to aqueous aerosol is a major loss channel for nitrogen oxides in the troposphere. Despite its importance, a quantitative picture of the uptake mechanism is missing. Here we use molecular dynamics simulations with a data-driven many-body model of coupled-cluster accuracy to quantify thermodynamics and kinetics of solvation and adsorption of N2O5 in water. The free energy profile highlights that N2O5 is selectively adsorbed to the liquid-vapor interface and weakly solvated. Accommodation into bulk water occurs slowly, competing with evaporation upon adsorption from gas phase. Leveraging the quantitative accuracy of the model, we parameterize and solve a reaction-diffusion equation to determine hydrolysis rates consistent with experimental observations. We find a short reaction-diffusion length, indicating that the uptake is dominated by interfacial features. The parameters deduced here, including solubility, accommodation coefficient, and hydrolysis rate, afford a foundation for which to consider the reactive loss of N2O5 in more complex solutions.

DFT Calculations for Mössbauer Properties on Dinuclear Center Models of the Resting Oxidized Cytochrome c Oxidase.

Mössbauer isomer shift and quadrupole splitting properties have been calculated using the OLYP-D3(BJ) density functional method on previously obtained (W.-G. Han Du, et al., Inorg Chem. 2020, 59, 8906-8915) geometry optimized Fea33+ -H2 O-CuB2+ dinuclear center (DNC) clusters of the resting oxidized (O state) "as-isolated" cytochrome c oxidase (CcO). The calculated results are highly consistent with the available experimental observations. The calculations have also shown that the structural heterogeneities of the O state DNCs implicated by the Mössbauer experiments are likely consequences of various factors, particularly the variable positions of the central H2 O molecule between the Fea33+ and CuB2+ sites in different DNCs, whether or not this central H2 O molecule has H-bonding interaction with another H2 O molecule, the different spin states having similar energies for the Fea33+ sites, and whether the Fea33+ and CuB2+ sites are ferromagnetically or antiferromagnetically spin-coupled.

MB-Fit: Software infrastructure for data-driven many-body potential energy functions.

Many-body potential energy functions (MB-PEFs), which integrate data-driven representations of many-body short-range quantum mechanical interactions with physics-based representations of many-body polarization and long-range interactions, have recently been shown to provide high accuracy in the description of molecular interactions from the gas to the condensed phase. Here, we present MB-Fit, a software infrastructure for the automated development of MB-PEFs for generic molecules within the TTM-nrg (Thole-type model energy) and MB-nrg (many-body energy) theoretical frameworks. Besides providing all the necessary computational tools for generating TTM-nrg and MB-nrg PEFs, MB-Fit provides a seamless interface with the MBX software, a many-body energy and force calculator for computer simulations. Given the demonstrated accuracy of the MB-PEFs, particularly within the MB-nrg framework, we believe that MB-Fit will enable routine predictive computer simulations of generic (small) molecules in the gas, liquid, and solid phases, including, but not limited to, the modeling of quantum isomeric equilibria in molecular clusters, solvation processes, molecular crystals, and phase diagrams.

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 and library 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.

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 four GPU nodes, each containing four NVIDIA V100-SXM2 type GPUs demonstrate that our implementation is capable of achieving excellent load balancing and high parallel efficiency. For representative medium to large size protein/organic molecular systems, the observed parallel efficiencies remained above 82% for the Kohn-Sham matrix formation and above 90% for nuclear gradient calculations. The accelerations on NVIDIA A100, P100, and K80 platforms also have realized parallel efficiencies higher than 68% in all tested cases, paving the way for large-scale ab initio electronic structure calculations with QUICK.

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 a 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 nonreactive 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 the 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.

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 in bulk water, the N-methylacetamide (NMA) molecule and the photoactive yellow protein (PYP), 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 53× between a single GPU vs a single CPU core and of up to 2.6× when comparing four GPUs to a single GPU. Results also reveal speedups of up to 3.5× when the API is used instead of FBI.

Coupled transport of electrons and protons in a bacterial cytochrome c oxidase-DFT calculated properties compared to structures and spectroscopies.

After a general introduction to the features and mechanisms of cytochrome c oxidases (CcOs) in mitochondria and aerobic bacteria, we present DFT calculated physical and spectroscopic properties for the catalytic reaction cycle compared with experimental observations in bacterial ba3 type CcO, also with comparisons/contrasts to aa3 type CcOs. The Dinuclear Complex (DNC) is the active catalytic reaction center, containing a heme a3 Fe center and a near lying Cu center (called CuB) where by successive reduction and protonation, molecular O2 is transformed to two H2O molecules, and protons are pumped from an inner region across the membrane to an outer region by transit through the CcO integral membrane protein. Structures, energies and vibrational frequencies for Fe-O and O-O modes are calculated by DFT over the catalytic cycle. The calculated DFT frequencies in the DNC of CcO are compared with measured frequencies from Resonance Raman spectroscopy to clarify the composition, geometry, and electronic structures of different intermediates through the reaction cycle, and to trace reaction pathways. X-ray structures of the resting oxidized state are analyzed with reference to the known experimental reaction chemistry and using DFT calculated structures in fitting observed electron density maps. Our calculations lead to a new proposed reaction pathway for coupling the PR → F → OH (ferryl-oxo → ferric-hydroxo) pathway to proton pumping by a water shift mechanism. Through this arc of the catalytic cycle, major shifts in pKa's of the special tyrosine and a histidine near the upper water pool activate proton transfer. Additional mechanisms for proton pumping are explored, and the role of the CuB+ (cuprous state) in controlling access to the dinuclear reaction site is proposed.

ReaxFF/AMBER-A Framework for Hybrid Reactive/Nonreactive Force Field Molecular Dynamics Simulations.

Combined quantum mechanical/molecular mechanical (QM/MM) models using semiempirical and ab initio methods have been extensively reported on over the past few decades. These methods have been shown to be capable of providing unique insights into a range of problems, but they are still limited to relatively short time scales, especially QM/MM models using ab initio methods. An intermediate approach between a QM based model and classical mechanics could help fill this time-scale gap and facilitate the study of a range of interesting problems. Reactive force fields represent the intermediate approach explored in this paper. A widely used reactive model is ReaxFF, which has largely been applied to materials science problems and is generally used as a stand-alone (i.e., the full system is modeled using ReaxFF). We report a hybrid ReaxFF/AMBER molecular dynamics (MD) tool, which introduces ReaxFF capabilities to capture bond breaking and formation within the AMBER MD software package. This tool enables us to study local reactive events in large systems at a fraction of the computational costs of QM/MM models. We describe the implementation of ReaxFF/AMBER, validate this implementation using a benzene molecule solvated in water, and compare its performance against a range of similar approaches. To illustrate the predictive capabilities of ReaxFF/AMBER, we carried out a Claisen rearrangement study in aqueous solution. In a first for ReaxFF, we were able to use AMBER's potential of mean force (PMF) capabilities to perform a PMF study on this organic reaction. The ability to capture local reaction events in large systems using combined ReaxFF/AMBER opens up a range of problems that can be tackled using this model to address both chemical and biological processes.

Solvation Free Energies and Adsorption Energies at the Metal/Water Interface from Hybrid Quantum-Mechanical/Molecular Mechanics Simulations.

Modeling adsorption at metal/water interfaces is a cornerstone toward an improved understanding in a variety of fields from heterogeneous catalysis to corrosion. We propose and validate a hybrid scheme that combines the adsorption free energies obtained in the gas phase at the density functional theory level with the variation in solvation from the bulk phase to the interface evaluated using a MM-based alchemical transformation, denoted MMsolv. Using the GAL17 force field for the platinum/water interaction, we retrieve a qualitatively correct interaction energy of the water solvent at the interface. This interaction is of near chemisorption character and thus challenging, both for the alchemical transformation and also for the fixed point-charge electrostatics. Our scheme passes through a state characterized by a well-behaved physisorption potential for the Pt(111)/H2O interaction to converge the free energy difference. The workflow is implemented in the freely available SolvHybrid package. We first assess the adsorption of a water molecule at the Pt/water interface, which turns out to be a stringent test. The intrinsic error of our quantum-mechanical/molecular mechanics (QM/MM) hybrid scheme is limited to 6 kcal mol-1 through the introduction of a correction term to attenuate the electrostatic interaction between near-chemisorbed water molecules and the underlying Pt atoms. Next, we show that the MMsolv solvation free energy of Pt (-0.46 J m-2) is in good agreement with the experimental estimate (-0.32 J m-2). Furthermore, we show that the entropy contribution at room temperature is roughly of equal magnitude as the free energy but with an opposite sign. Finally, we compute the adsorption energy of benzene and phenol at the Pt(111)/water interface, one of the rare systems for which experimental data are available. In qualitative agreement with the experiment, but in stark contrast with a standard implicit solvent model, the adsorption of these aromatic molecules is strongly reduced (i.e., less exothermic by ∼30 and 40 kcal mol-1 for our QM/MM hybrid scheme and experiment, respectively, but ∼0 with the implicit solvent) at the solid/liquid interface compared to the solid/gas interface. This reduction occurs mainly because of the competition between the organic adsorbate and the solvent for adsorption on the metallic surface. The semiquantitative agreement with experimental estimates for the adsorption energy of aromatic molecules thus validates the soundness of our hybrid QM/MM scheme.

Parallel Implementation of Density Functional Theory Methods in the Quantum Interaction Computational Kernel Program.

We present the details of a graphics processing unit (GPU) capable exchange correlation (XC) scheme integrated into the open source QUantum Interaction Computational Kernel (QUICK) program. Our implementation features an octree based numerical grid point partitioning scheme, GPU enabled grid pruning and basis and primitive function prescreening, and fully GPU capable XC energy and gradient algorithms. Benchmarking against the CPU version demonstrated that the GPU implementation is capable of delivering an impressive performance while retaining excellent accuracy. For small to medium size protein/organic molecular systems, the realized speedups in double precision XC energy and gradient computation on a NVIDIA V100 GPU were 60-80-fold and 140-500-fold, respectively, as compared to the serial CPU implementation. The acceleration gained in density functional theory calculations from a single V100 GPU significantly exceeds that of a modern CPU with 40 cores running in parallel.

A Water Molecule Residing in the Fea33+···CuB2+ Dinuclear Center of the Resting Oxidized as-Isolated Cytochrome c Oxidase: A Density Functional Study.

Although the dinuclear center (DNC) of the resting oxidized "as-isolated" cytochrome c oxidase (CcO) is not a catalytically active state, its detailed structure, especially the nature of the bridging species between the Fea33+ and CuB2+ metal sites, is still both relevant and unsolved. Recent crystallographic work has shown an extended electron density for a peroxide type dioxygen species (O1-O2) bridging the Fea3 and CuB centers. In this paper, our density functional theory (DFT) calculations show that the observed peroxide type electron density between the two metal centers is most likely a mistaken analysis due to overlap of the electron density of a water molecule located at different positions between apparent O1 and O2 sites in DNCs of different CcO molecules with almost the same energy. Because the diffraction pattern and the resulting electron density map represent the effective long-range order averaged over many molecules and unit cells in the X-ray structure, this averaging can lead to an apparent observed superposition of different water positions between the Fea33+ and CuB2+ metal sites.