Improved Sampling of Adaptive Path Collective Variables by Stabilized Extended-System Dynamics

Because of the complicated multistep nature of many biocatalytic reactions, an a priori definition of reaction coordinates is difficult. Therefore, we apply enhanced sampling algorithms along with adaptive path collective variables (PCVs), which converge to the minimum free energy path (MFEP) during the simulation. We show how PCVs can be combined with the highly efficient well-tempered metadynamics extended-system adaptive biasing force (WTM-eABF) hybrid sampling algorithm, offering dramatically increased sampling efficiency due to its fast adaptation to path updates. For this purpose, we address discontinuities of PCVs that can arise due to path shortcutting or path updates with a novel stabilization algorithm for extended-system methods. In addition, we show how the convergence of simulations can be further accelerated by utilizing the multistate Bennett’s acceptance ratio (MBAR) estimator. These methods are applied to the first step of the enzymatic reaction mechanism of pseudouridine synthases, where the ability of path WTM-eABF to efficiently explore intricate molecular transitions is demonstrated

Influence of Coupling and Embedding Schemes on QM Size Convergence in QM/MM Approaches for the Example of a Proton Transfer in DNA

The influence of embedding and coupling schemes on the convergence of the QM size in the QM/MM approach is investigated for the transfer of a proton in a DNA base pair. We find that the embedding scheme (mechanical or electrostatic) has a much greater impact on the convergence behavior than the coupling scheme (additive QM/MM or subtractive ONIOM). To achieve size convergence, QM regions with up to 6000 atoms are necessary for pure QM or mechanical embedding. In contrast, electrostatic embedding converges faster: for the example of the transfer of a proton between DNA base pairs, we recommend including at least five base pairs and 5 Å of solvent (including counterions) into the QM region, i.e., a total of 1150 atoms

Quantum-Chemical Study of the Discrimination against dNTP in the Nucleotide Addition Reaction in the Active Site of RNA Polymerase II

Eukaryotic RNA polymerase II catalyzes the transcription of DNA into mRNA very efficiently and with an extremely low error rate with regard to matching base and sugar moiety. Despite its importance, little is known about how it discriminates against 2′-deoxy NTPs during the chemical reaction. To investigate the differences in the addition reactions of ATP and dATP, we used FF-MD and QM/MM calculations within a nudged elastic band approach, which allowed us to find the energetically accessible reaction coordinates. By converging the QM size, we found that 800 QM atoms are necessary to properly describe the active site. We show how the absence of a single hydrogen bond between the enzyme and the NTP 2′-OH group leads to an increase of the reaction barrier by 16 kcal/mol and therefore conclude that Arg446 is the key residue in the discrimination process

Improved Sampling of Adaptive Path Collective Variables by Stabilized Extended-System Dynamics

Because of the complicated multistep nature of many biocatalytic reactions, an a priori definition of reaction coordinates is difficult. Therefore, we apply enhanced sampling algorithms along with adaptive path collective variables (PCVs), which converge to the minimum free energy path (MFEP) during the simulation. We show how PCVs can be combined with the highly efficient well-tempered metadynamics extended-system adaptive biasing force (WTM-eABF) hybrid sampling algorithm, offering dramatically increased sampling efficiency due to its fast adaptation to path updates. For this purpose, we address discontinuities of PCVs that can arise due to path shortcutting or path updates with a novel stabilization algorithm for extended-system methods. In addition, we show how the convergence of simulations can be further accelerated by utilizing the multistate Bennett’s acceptance ratio (MBAR) estimator. These methods are applied to the first step of the enzymatic reaction mechanism of pseudouridine synthases, where the ability of path WTM-eABF to efficiently explore intricate molecular transitions is demonstrated

Hybrid CPU/GPU Integral Engine for Strong-Scaling <i>Ab Initio</i> Methods

We present a parallel integral algorithm for two-electron contributions occurring in Hartree–Fock and hybrid density functional theory that allows for a strong scaling parallelization on inhomogeneous compute clusters. With a particular focus on graphic processing units, we show that our approach allows an efficient use of CPUs and graphics processing units (GPUs) simultaneously, although the different architectures demand conflictive strategies in order to ensure efficient program execution. Furthermore, we present a general strategy to use large basis sets like quadruple-ζ split valence on GPUs and investigate the balance between CPUs and GPUs depending on <i>l</i>-quantum numbers of the corresponding basis functions. Finally, we present first illustrative calculations using a hybrid CPU/GPU environment and demonstrate the strong-scaling performance of our parallelization strategy also for pure CPU-based calculations

Spin Component-Scaled Second-Order Møller–Plesset Perturbation Theory for Calculating NMR Shieldings

Spin component-scaled and scaled opposite-spin second-order Møller–Plesset perturbation approaches (SCS-MP2 and SOS-MP2) are introduced for calculating NMR chemical shifts in analogy to the well-established scaled approaches for MP2 energies. Gauge-including atomic orbitals (GIAO) are employed throughout this work. The GIAO-SCS-MP2 and GIAO-SOS-MP2 methods typically show superior performance to nonscaled MP2 and are closer to the coupled-cluster singles doubles perturbative triples (CCSD­(T))/cc-pVQZ reference values. In addition, the pragmatic use of mixed basis sets for the Hartree–Fock and the correlated part of NMR chemical shift calculations is shown to be beneficial

Convergence of Electronic Structure with the Size of the QM Region: Example of QM/MM NMR Shieldings

The influence of the chemical environment on NMR shifts of a central molecular region is studied for several biomolecular and supramolecular systems. To investigate the long-range effects, we systematically increase the QM region until the changes of the NMR shielding tensor are negligible for the considered nuclei; that is, convergence with the selected QM size is reached. To reach size convergence, QM regions with up to about 1500 atoms and 15 000 basis functions are treated by our density matrix-based linear-scaling coupled perturbed self-consistent field methods. The results also provide insights into the locality and convergence of the electronic structure. Furthermore, we demonstrate to what extent the inclusion of the chemical environment as partial point charges within a hybrid QM/MM approach improves the convergence behavior. In addition, some benchmark data on NMR accuracies are provided using various ab initio methods

A Dynamic Equilibrium of Three Hydrogen-Bond Conformers Explains the NMR Spectrum of the Active Site of Photoactive Yellow Protein

A theoretical study on the NMR shifts of the hydrogen bond network around the chromophore, para-coumaric acid (<i>p</i>CA), of photoactive yellow protein (PYP) is presented. Previous discrepancies between theoretical and experimental studies are resolved by our findings of a previously unknown rapid conformational exchange near the active site of PYP. This exchange caused by the rotation of Thr50 takes place in the ground state of PYP’s active site and results in three effectively energetically equal conformations characterized by the formation of new hydrogen bonds, all of which contribute to the overall NMR signals of the investigated protons. In light of these findings, we are able to successfully explain the experimental results and provide valuable insight into the behavior of PYP in solution. We further investigated related PYP mutants (T50V, E46Q, and Y42F), and found the same conformational exchange in E46Q and Y42F to be responsible for the experimentally observed NMR and UV/vis spectra

Efficient and Accurate Born–Oppenheimer Molecular Dynamics for Large Molecular Systems

An efficient scheme for the calculation of Born–Oppenheimer molecular dynamics (BOMD) simulations is introduced. It combines the corrected small basis set Hartree–Fock (HF-3c) method by Sure and Grimme [<i>J. Comput. Chem.</i> <b>2013</b>, 43, 1672], extended Lagrangian BOMD (XL-BOMD) by Niklasson et al. [<i>J. Chem. Phys.</i> <b>2009</b>, 130, 214109], and the calculation of the two electron integrals on graphics processing units (GPUs) [<i>J. Chem. Phys.</i> <b>2013</b>, 138, 134114; <i>J. Chem. Theory Comput.</i> <b>2015</b>, 11, 918]. To explore the parallel performance of our strong scaling implementation of the method, we present timings and extract, as its validation and first illustrative application, high-quality vibrational spectra from simulated trajectories of β-carotene, paclitaxel, and liquid water (up to 500 atoms). We conclude that the presented BOMD scheme may be used as a cost-efficient and reliable tool for computing vibrational spectra and thermodynamics of large molecular systems including explicit solvent molecules containing 500 atoms and more. Simulating 50 ps of maitotoxin (nearly 500 atoms) employing time steps of 0.5 fs requires ∼3 weeks on 12 CPUs (Intel Xeon E5 2620 v3) with 24 GPUs (AMD FirePro 3D W8100)

Sensitivity of ab Initio vs Empirical Methods in Computing Structural Effects on NMR Chemical Shifts for the Example of Peptides

The structural sensitivity of NMR chemical shifts as computed by quantum chemical methods is compared to a variety of empirical approaches for the example of a prototypical peptide, the 38-residue kaliotoxin <i>KTX</i> comprising 573 atoms. Despite the simplicity of empirical chemical shift prediction programs, the agreement with experimental results is rather good, underlining their usefulness. However, we show in our present work that they are highly insensitive to structural changes, which renders their use for validating predicted structures questionable. In contrast, quantum chemical methods show the expected high sensitivity to structural and electronic changes. This appears to be independent of the quantum chemical approach or the inclusion of solvent effects. For the latter, explicit solvent simulations with increasing number of snapshots were performed for two conformers of an eight amino acid sequence. In conclusion, the empirical approaches neither provide the expected magnitude nor the patterns of NMR chemical shifts determined by the clearly more costly ab initio methods upon structural changes. This restricts the use of empirical prediction programs in studies where peptide and protein structures are utilized for the NMR chemical shift evaluation such as in NMR refinement processes, structural model verifications, or calculations of NMR nuclear spin relaxation rates