Investigating the Substrate Oxidation Mechanism in Lytic Polysaccharide Monooxygenase: HO- versus O-Activation.

Lytic polysaccharide monooxygenases (LPMOs) form a copper-dependent family of enzymes classified under the auxiliary activity (AA) superfamily. The LPMOs are known for their boosting of polysaccharide degradation through oxidation of the glycosidic bonds that link the monosaccharide subunits. This oxidation has been proposed to be dependent on either O or HO as cosubstrate.

Perspective: multi-configurational methods in bio-inorganic chemistry.

Transition metal ions play crucial roles in the structure and function of numerous proteins, contributing to essential biological processes such as catalysis, electron transfer, and oxygen binding. However, accurately modeling the electronic structure and properties of metalloproteins poses significant challenges due to the complex nature of their electronic configurations and strong correlation effects. Multiconfigurational quantum chemistry methods are, in principle, the most appropriate tools for addressing these challenges, offering the capability to capture the inherent multi-reference character and strong electron correlation present in bio-inorganic systems.

Simulating X-ray Absorption Spectroscopy in Challenging Environments: Methodological Insights from Water-Solvated Ammonia and Ammonium Systems.

Core-electron excitations in solvated systems, influenced by solvent geometry and hydrogen bonding, make X-ray absorption spectroscopy (XAS) a valuable tool for assessing solvent-solute interactions. However, calculating XAS spectra with electronic-structure methods has proven challenging due to a delicate interplay between correlation and solvation effects. This study provides a computational procedure for XAS modeling in solvated systems, with water-solvated ammonia and ammonium systems serving as probes.

A frontier-orbital view of the initial steps of lytic polysaccharide monooxygenase reactions.

Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes that oxidatively cleave the strong C-H bonds in recalcitrant polysaccharide substrates, thereby playing a crucial role in biomass degradation. Recently, LPMOs have also been shown to be important for several pathogens. It is well established that the Cu(II) resting state of LPMOs is inactive, and the electronic structure of the active site needs to be altered to transform the enzyme into an active form.

Understanding the initial events of the oxidative damage and protection mechanisms of the AA9 lytic polysaccharide monooxygenase family.

Lytic polysaccharide monooxygenase (LPMO) is a new class of oxidoreductases that boosts polysaccharide degradation employing a copper active site. This boost may facilitate the cost-efficient production of biofuels and high-value chemicals from polysaccharides such as lignocellulose. Unfortunately, self-oxidation of the active site inactivates LPMOs.

Accuracy of One- and Two-Photon Intensities with the Extended Polarizable Density Embedding Model.

The recently developed extended polarizable density embedding (PDE-X) model is evaluated for the spectroscopic properties of organic chromophores solvated in water, including both one- and two-photon absorption properties. The PDE-X embedding model systematically improves vertical excitation energies over the preceding polarizable density embedding model (PDE). PDE-X shows more modest improvements over existing embedding models for oscillator strengths and two-photon absorption cross-sections, which are more sensitive properties.

Theoretical and Numerical Comparison of Quantum- and Classical Embedding Models for Optical Spectra.

Quantum-mechanical (QM) and classical embedding models approximate a supermolecular quantum-chemical calculation. This is particularly useful when the supermolecular calculation has a size that is out of reach for present QM models. Although QM and classical embedding methods share the same goal, they approach this goal from different starting points.

Histidine oxidation in lytic polysaccharide monooxygenase.

The lytic polysaccharide monooxygenases (LPMOs) comprise a super-family of copper enzymes that boost the depolymerisation of polysaccharides by oxidatively disrupting the glycosidic bonds connecting the sugar units. Industrial use of LPMOs for cellulose depolymerisation has already begun but is still far from reaching its full potential. One issue is that the LPMOs self-oxidise and thereby deactivate.

A method to capture the large relativistic and solvent effects on the UV-vis spectra of photo-activated metal complexes.

We have recently developed a method based on relativistic time-dependent density functional theory (TD-DFT) that allows the calculation of electronic spectra in solution (Creutzberg, Hedegård, , 2022, 3671). This method treats the solvent explicitly with a classical, polarizable embedding (PE) description. Furthermore, it employs the complex polarization propagator (CPP) formalism which allows calculations on complexes with a dense population of electronic states (such complexes are known to be problematic for conventional TD-DFT).

Nuclear Magnetic Shielding Constants with the Polarizable Density Embedding Model.

We extend the polarizable density embedding (PDE) model to support the calculation of nuclear magnetic resonance (NMR) shielding constants using gauge-including atomic orbitals (GIAOs) within a density functional theory (DFT) framework. The PDE model divides the total system into fragments, describing some by quantum mechanics (QM) and the others through an embedding model. The PDE model uses anisotropic polarizabilities, inter-fragment two-electron Coulomb integrals, and a non-local repulsion operator to emulate the QM effects.

Multiconfigurational short-range density functional theory for nuclear magnetic resonance shielding constants with gauge-including atomic orbitals.

In this paper, we present the theory and implementation of nuclear magnetic resonance shielding constants with gauge-including atomic orbitals for the hybrid multiconfigurational short-range density functional theory model. As a special case, this implementation also includes Hartree-Fock srDFT (HF-srDFT). Choosing a complete-active space (CAS) wave function as the multiconfigurational parameterization of the wave function, we investigate how well CAS-srDFT reproduces experimental trends of nuclear shielding constants compared to DFT and complete active space self-consistent field (CASSCF).

New relativistic quantum chemical methods for understanding light-induced therapeutics.

The inorganic platinum complexes currently in clinical use for cancer treatment have severe side effects, and complexes with fewer side effects are required. One option is to use complexes that are inactive until they are light-activated. Theoretical chemistry can contribute to the design of these complexes, but most current theoretical methods lack explicit treatment of relativistic effects (since the target complexes often contain heavy elements).

Molecular Mechanism of Substrate Oxidation in Lytic Polysaccharide Monooxygenases: Insight from Theoretical Investigations.

Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes that today comprise a large enzyme superfamily, grouped into the distinct members AA9-AA17 (with AA12 exempted). The LPMOs have the potential to facilitate the upcycling of biomass waste products by boosting the breakdown of cellulose and other recalcitrant polysaccharides. The cellulose biopolymer is the main component of biomass waste and thus comprises a large, unexploited resource.

Fragmentation-Based Decomposition of a Metalloenzyme-Substrate Interaction: A Case Study for a Lytic Polysaccharide Monooxygenase.

We present a novel decomposition scheme for electronic interaction energies based on the flexible formulation of fragmentation schemes through fragment combination ranges (FCRs; , , , 164105). We devise a clear additive decomposition with contribution of nondisjoint fragments and correction terms for overlapping fragments and apply this scheme to the metalloenzyme-substrate complex of a lytic polysaccharide monooxygenase (LPMO) with an oligosaccharide. By this, we further illustrate the straightforward adaptability of the FCR-based schemes to novel systems.

Polarizable Embedding Complex Polarization Propagator in Four- and Two-Component Frameworks.

Explicit embedding methods combined with the complex polarization propagator (CPP) enable the modeling of spectroscopy for increasingly complex systems with a high density of states. We present the first derivation and implementation of the CPP in four- and exact-two-component (X2C) polarizable embedding (PE) frameworks. We denote the developed methods PE-4c-CPP and PE-X2C-CPP, respectively.

The role of the active site tyrosine in the mechanism of lytic polysaccharide monooxygenase.

Catalytic breakdown of polysaccharides can be achieved more efficiently by means of the enzymes lytic polysaccharide monooxygenases (LPMOs). However, the LPMO mechanism has remained controversial, preventing full exploitation of their potential. One of the controversies has centered around an active site tyrosine, present in most LPMO classes.

Estimating the accuracy of calculated electron paramagnetic resonance hyperfine couplings for a lytic polysaccharide monooxygenase.

Lytic polysaccharide monooxygenases (LPMOs) are enzymes that bind polysaccharides followed by an (oxidative) disruption of the polysaccharide surface, thereby boosting depolymerization. The binding process between the LPMO catalytic domain and polysaccharide is key to the mechanism and establishing structure-function relationships for this binding is therefore crucial. The hyperfine coupling constants (HFCs) from EPR spectroscopy have proven useful for this purpose.

Engineering the Oxidative Potency of Non-Heme Iron(IV) Oxo Complexes in Water for C-H Oxidation by a Donor and Variation of the Second Coordination Sphere.

A series of iron(IV) oxo complexes, which differ in the donor (CHpy or CHCOO) to the oxo group, three with hemilabile pendant donor/second coordination sphere base/acid arms (pyH/py or ROH), have been prepared in water at pH 2 and 7. The ν values of 832 ± 2 cm indicate similar Fe═O bond strengths; however, different reactivities toward C-H substrates in water are observed. HAT occurs at rates that differ by 1 order of magnitude with nonclassical KIEs ( = 30-66) consistent with hydrogen atom tunneling.

Investigating the influence of relativistic effects on absorption spectra for platinum complexes with light-activated activity against cancer cells.

We report the first systematic investigation of relativistic effects on the UV-vis spectra of two prototype complexes for so-called photo-activated chemotherapy (PACT), trans-trans-trans-[Pt(N3)2(OH)2(NH3)2] and cis-trans-cis-[Pt(N3)2(OH)2(NH3)2]. In PACT, design of new drugs requires in-depth understanding of the photo-activation mechanisms. A first step is usually to rationalize their UV-vis spectra for which time-dependent density functional theory (TD-DFT) is an indispensable tool.

Dalton Project: A Python platform for molecular- and electronic-structure simulations of complex systems.

The Dalton Project provides a uniform platform access to the underlying full-fledged quantum chemistry codes Dalton and LSDalton as well as the PyFraME package for automatized fragmentation and parameterization of complex molecular environments. The platform is written in Python and defines a means for library communication and interaction. Intermediate data such as integrals are exposed to the platform and made accessible to the user in the form of NumPy arrays, and the resulting data are extracted, analyzed, and visualized.

The DIRAC code for relativistic molecular calculations.

DIRAC is a freely distributed general-purpose program system for one-, two-, and four-component relativistic molecular calculations at the level of Hartree-Fock, Kohn-Sham (including range-separated theory), multiconfigurational self-consistent-field, multireference configuration interaction, electron propagator, and various flavors of coupled cluster theory. At the self-consistent-field level, a highly original scheme, based on quaternion algebra, is implemented for the treatment of both spatial and time reversal symmetry. DIRAC features a very general module for the calculation of molecular properties that to a large extent may be defined by the user and further analyzed through a powerful visualization module.

Is density functional theory accurate for lytic polysaccharide monooxygenase enzymes?

The lytic polysaccharide monooxygenase (LPMO) enzymes boost polysaccharide depolymerization through oxidative chemistry, which has fueled the hope for more energy-efficient production of biofuel. We have recently proposed a mechanism for the oxidation of the polysaccharide substrate (E. D.

Triplet excitation energies from multiconfigurational short-range density-functional theory response calculations.

Linear response theory for the multiconfigurational short-range density functional theory (MC-srDFT) model is extended to triplet response with a singlet reference wave function. The triplet linear response equations for MC-srDFT are derived for a general hybrid srGGA functional and implemented in the Dalton program. Triplet excitation energies are benchmarked against the CC3 model of coupled cluster theory and the complete-active-space second-order perturbation theory using three different short-range functionals (srLDA, srPBE, and srPBE0), both with full linear response and employing the generalized Tamm-Dancoff approximation (gTDA).

Mechanism of hydrogen peroxide formation by lytic polysaccharide monooxygenase.

Lytic polysaccharide monooxygenases (LPMOs) are copper-containing metalloenzymes that can cleave the glycosidic link in polysaccharides. This could become crucial for production of energy-efficient biofuels from recalcitrant polysaccharides. Although LPMOs are considered oxygenases, recent investigations have shown that HO can also act as a co-substrate for LPMOs.