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

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

Unraveling the Base Excision Repair Mechanism of Human DNA Glycosylase

Human DNA glycosylase, hOGG1, is known to perform DNA repair by cleaving oxidized guanine (8OG) from the DNA. Despite numerous experimental and theoretical investigations, the underlying selective molecular mechanism has remained a mystery. Here we present a mechanism that explains how hOGG1’s catalytic pocket is able to host an undamaged guanine base, but is not able to cleave it from the DNA. Using linear-scaling quantum mechanics/molecular mechanics (QM/MM) techniques with more than 500 atoms in the QM-region, we have investigated previously proposed mechanisms that all rely on protonating the 8OG nucleobase. We have found that the repair mechanisms propagated in the literature to this date are not capable of differentiating between the G and 8OG nucleobase. Besides this nonselectivity, they also involve reaction barriers that are too high, hence rendering the corresponding reaction intermediates inaccessible. Instead, we present a completely different reaction mechanism, where hOGG1 initially targets the ribose moiety of the substrate and cleaves the glycosidic bond at the very last stage. Our ribose-protonated repair mechanism is not only energetically more preferable, but also explains the selectivity utilized by hOGG1 to block processing a guanine base

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

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

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

A Convergence Study of QM/MM Isomerization Energies with the Selected Size of the QM Region for Peptidic Systems

A systematic study of the convergence of QM/MM results with respect to the chosen size of the QM region is presented for two examples of peptidic systems. For this purpose, we increased the QM region to up to 1637 atoms at the HF/SVP and 383 atoms at the SOS-AO-MP2/6-31G** level. While the convergence behavior is almost independent of the chosen method and basis set, the study clearly shows that for the considered proton-transfer energy the QM/MM treatment leads to a significantly faster convergence than the pure QM treatment. This behavior can be rationalized by the fair description of the surrounding of the active center using MM methods, even though the MM description of the active center is not adequate in our present case. At the same time, the observed convergence is quite insensitive to a variation of charge surroundings in the chosen model peptides. Although the QM/MM results do converge much quicker with the system size than the pure QM ones, the data show that even for the chosen simple model systems about 150300 QM atoms are needed to achieve accuracies in the order of 10 kJ/mol and about 3001000 atoms for an accuracy of 2 kJ/mol with respect to a convergence with the QM-region size

Highly Efficient and Accurate Computation of Multiple Orbital Spaces Spanning Fock Matrix Elements on Central and Graphics Processing Units for Application in F12 Theory

We employ our recently published highly efficient seminumerical exchange (sn-LinK) [Laqua, H.; Thompson, T. H.; Kussmann, J.; Ochsenfeld, C. J. Chem. Theory Comput. 2020, 16, 1456−1468] and integral-direct resolution of the identity Coulomb (RI-J) [Kussmann, J.; Laqua, H.; Ochsenfeld, C. J. Chem. Theory Comput. 2021, 17, 1512−1521] methods to significantly accelerate the computation of the demanding multiple orbital spaces spanning Fock matrix elements present in R12/F12 theory on central and graphics processing units. The errors introduced by RI-J and sn-LinK into the RI-MP2-F12 energy are thoroughly assessed for a variety of basis sets and integration grids. We find that these numerical errors are always below “chemical accuracy” (∼1 mH) even for the coarsest settings and can easily be reduced below 1 μH by employing only moderately large integration grids and RI-J basis sets. Since the number of basis functions of the multiple orbital spaces is notably larger compared with conventional Hartree–Fock theory, the efficiency gains from the superior basis scaling of RI-J and sn-LinK (O(Nbas2) instead of O(Nbas4) for both) are even more significant, with maximum speedup factors of 37 000 for RI-J and 4500 for sn-LinK. In total, the multiple orbital spaces spanning Fock matrix evaluation of the largest tested structure using a triple-ζ F12 basis set (5058 AO basis functions, 9267 CABS basis functions) is accelerated over 1575× using CPUs and over 4155× employing GPUs