Exploring solvatochromism: A comprehensive analysis of research data

Microchemical Journal, Год журнала: 2024, Номер 198, С. 110166 - 110166

Опубликована: Фев. 13, 2024

Язык: Английский

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Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(10), С. 6983 - 6991

Опубликована: Фев. 28, 2024

Molecular dynamics (MD) simulations are frequently carried out for proteins to investigate the role of electrostatics in their biological function. The choice force field (FF) can significantly alter MD results, as simulated local electrostatic interactions lack benchmarking absence appropriate experimental methods. We recently reported that transition dipole moment (TDM) popular nitrile vibrational probe varies linearly with environmental electric field, overcoming well-known hydrogen bonding (H-bonding) issues frequency and, thus, enabling unambiguous measurement fields (J. Am. Chem. Soc. 2022, 144 (17), 7562–7567). Herein, we utilize this new strategy enable comparisons and protein environments. Specifically, previously determined TDM exerted onto nitrile-containing o-cyanophenylalanine residues photoactive yellow compared from fixed-charge AMBER FF polarizable AMOEBA FF. observe distributions H-bonding nitriles substantially affected by As such, underestimates experiencing moderate strengths; contrast, robustly recapitulates fields. dependence be partly explained presence additional negative charge density along bond axis AMOEBA, which is due inclusion higher-order multipole parameters; this, turn, begets more head-on H-bonds. conclude discussing implications simulation general.

Язык: Английский

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Local Electric Fields Drives the Proton-Coupled Electron Transfer within Cytochrome P450 Reductase

ACS Catalysis, Год журнала: 2024, Номер 14(10), С. 7893 - 7900

Опубликована: Май 6, 2024

Cytochrome P450 enzymes play a pivotal role in biosynthetic and metabolic transformations. Especially, cytochrome reductase (CPR) acts as the key electron donor for oxygen activation by monoxygenases, but transfer mechanism within CPR is largely elusive. Here, extensive molecular dynamics (MD) quantum mechanics/molecular mechanics (QM/MM) calculations were performed to elucidate CPR's mechanism. We found that from FADH– FMN occurs through proton-coupled (PCET) Glu142 transfers proton via two-water-molecule chain, concurrent with FMN. The subsequent ET FADH• FMNH• involves an Asp675-mediated PCET process, where Ser457-assisted Asp675 coupled FMNH•. Notably, local electric field doubly protonated His180 significantly enhances reactions both kinetically thermodynamically. This study highlights vital of facilitating biological enzymatic reactions.

Язык: Английский

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Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases

ACS Catalysis, Год журнала: 2024, Номер 14(9), С. 7166 - 7172

Опубликована: Апрель 23, 2024

Resistance to antibiotics is a public health crisis. Although carbapenems are less susceptible resistance than other β-lactam antibiotics, β-lactamases mediating against these drugs spreading. Here, we dissect the contributions of electric fields carbapenemase activity in class A β-lactamases. We perform QM/MM molecular dynamics simulations meropenem acyl-enzyme hydrolysis that correctly discriminate carbapenemases. Electric field analysis shows active-site deacylation transition state and tetrahedral intermediate important determinants activity. The identify several residues, some distal, distinguish efficient Our script (www.github.com/bunzela/FieldTools) may help understanding combating antibiotic resistance.

Язык: Английский

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Long-Range Electrostatics in Serine Proteases: Machine Learning-Driven Reaction Sampling Yields Insights for Enzyme Design

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Computational enzyme design is a promising technique for producing novel enzymes industrial and clinical needs. A key challenge that this faces to consistently achieve the desired activity. Fundamental studies of natural revealed critical contributions from second-shell - even more distant residues their remarkable efficiency. In particular, such organize internal electrostatic field promote reaction. Engineering fields computationally proved be strategy, which, however, has some limitations. Charged necessarily form specific patterns local interactions may exploited structural integrity. As result, it impossible probe alone by substituting amino acids. We hypothesize an approach isolates influences residues' charges other could yield deeper insights. use molecular modeling with AI-enhanced QM/MM reaction sampling implement apply model serine protease subtilisin. find negative charge 8 Å away catalytic site crucial achieving enzyme's efficiency, contributing than 2 kcal/mol lowering barrier. contrast, positive second-closest charged residue opposes efficiency raising barrier 0.8 kcal/mol. This result invites discussion into role trade-offs might have taken place in evolution enzymes. Our transferable can help investigate preorganization believe study engineering direction advance both fundamental applied enzymology lead new powerful biocatalysts.

Язык: Английский

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Methods for Theoretical Treatment of Local Fields in Proteins and Enzymes

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Electric fields generated by protein scaffolds are crucial in enzymatic catalysis. This review surveys theoretical approaches for detecting, analyzing, and comparing electric fields, electrostatic potentials, their effects on the charge density within enzyme active sites. Pioneering methods like empirical valence bond approach rely evaluating ionic covalent resonance forms influenced field. Strategies employing polarizable force also facilitate field detection. The vibrational Stark effect connects computational simulations to experimental spectroscopy, enabling direct comparisons. We highlight how dynamics induce fluctuations local influencing activity. Recent techniques assess throughout site volume rather than only at specific bonds, machine learning helps relate these global reactivity. Quantum theory of atoms molecules captures entire electron landscape, providing a chemically intuitive perspective field-driven Overall, methodologies show protein-generated highly dynamic heterogeneous, understanding both aspects is critical elucidating mechanisms. holistic view empowers rational engineering tuning promising new avenues drug design, biocatalysis, industrial applications. Future directions include incorporating as explicit design targets enhance catalytic performance biochemical functionalities.

Язык: Английский

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PyCPET─Computing Heterogeneous 3D Protein Electric Fields and Their Dynamics

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

Electrostatic preorganization is an exciting mode to understand the catalytic function of enzymes, yet limited tools exist computationally analyze it. In particular, no methods interpret geometry, dynamics, and fundamental components 3D electric fields, E⃗(r), in protein active sites. To address this, we present PyCPET (Python Computation Electric Field Topologies), a comprehensive, open-source toolbox E⃗(r) enzymes. We designed it around computational efficiency user friendliness with both CPU- GPU-accelerated codes. Our aim provide set functions for rich, descriptive analysis enzyme systems including benchmarking, distribution streamlines computation point principal component analysis, visualization. Finally, demonstrate its versatility by exploring nature electrostatic dynamics three cases: Cytochrome C, Co-substituted Liver Alcohol Dehydrogenase, HIV Protease. These test systems, along previous work, establish as essential toolkit in-depth visualization fields unlocking new avenues understanding contributions catalysis.

Язык: Английский

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Physics-based modeling in the new era of enzyme engineering

Nature Computational Science, Год журнала: 2025, Номер 5(4), С. 279 - 291

Опубликована: Апрель 24, 2025

Язык: Английский

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Comprehensive analysis of nitrile probe IR shifts and intensities in proteins: experiment and critical evaluation of simulations

Опубликована: Янв. 2, 2024

Molecular dynamics (MD) simulations are frequently carried out for proteins to investigate the role of electrostatics in their biological function. The choice force field (FF) can significantly alter MD results as simulated local electrostatic interactions lack benchmarking absence appropriate experimental methods. We recently reported that transition dipole moment (TDM) popular nitrile vibrational probe varies linearly with environmental electric field, overcoming well-known hydrogen bonding (H-bonding) issues frequency and, thus, enabling unambiguous measurement fields (J. Am. Chem. Soc. 2022, 144 (17), 7562-7567). Herein, we utilize this new strategy enable comparisons and protein environments. Specifically, previously determined TDM exerted onto nitrile-containing o-cyanophenylalanine residues photoactive yellow compared from fixed-charge AMBER FF polarizable AMOEBA FF. observe distributions H-bonding nitriles substantially affected by As such, underestimates experiencing moderate strengths; contrast, robustly recapitulates fields. dependence be partly explained presence additional negative charge density along bond axis AMOEBA, which is due inclusion higher-order multipole parameters; turn begets more head-on H-bonds. conclude discussing implications simulation general.

Язык: Английский

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An algorithm to find the optimal oriented external electrostatic field for annihilating a reaction barrier in a polarizable molecular system

The Journal of Chemical Physics, Год журнала: 2023, Номер 159(11)

Опубликована: Сен. 19, 2023

The use of oriented external electric fields (OEEFs) to promote and control chemical reactivity has motivated many theoretical computational studies in the last decade model action OEEFs on a molecular system its effects processes. Given reaction, central goal this research area is predict optimal OEEF (oOEEF) required annihilate reaction energy barrier with smallest possible field strength. Here, we present rooted catastrophe optimum theories that allows us find oOEEF for given valley potential surface (PES). In model, effective (or perturbed) PES polarizable constructed by adding original, non-perturbed, term accounting interaction intrinsic dipole polarizability system, so called (PMED) model. We demonstrate can be established locating point original unique topological properties: breakdown or bond-breaking (oBBP). essential feature oBBP structure fact maintains properties all applied OEEFs, also unperturbed PES, thus becoming much more relevant than commonly used minima transition state structures. PMED proposed here been implemented an open access package shown successfully two processes: isomerization cumulene derivative Huisgen cycloaddition reaction.

Язык: Английский

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