Designed Local Electric Fields─Promising Tools for Enzyme Engineering

Abstract

Designing efficient catalysts is one of the ultimate goals of chemists. In this Perspective, we discuss how local electric fields (LEFs) can be exploited to improve the catalytic performance of supramolecular catalysts, such as enzymes. More specifically, this Perspective starts by laying out the fundamentals of how local electric fields affect chemical reactivity and review the computational tools available to study electric fields in various settings. Subsequently, the advances made so far in optimizing enzymatic electric fields through targeted mutations are discussed critically and concisely. The Perspective ends with an outlook on some anticipated evolutions of the field in the near future. Among others, we offer some pointers on how the recent data science/machine learning revolution, engulfing all science disciplines, could potentially provide robust and principled tools to facilitate rapid inference of electric field effects, as well as the translation between optimal electrostatic environments and corresponding chemical modifications.

Substrate Conformational Switch Enables the Stereoselective Dimerization in P450 NascB: Insights from Molecular Dynamics Simulations and Quantum Mechanical/Molecular Mechanical Calculations

“…In the previously suggested catalytic mechanism, the reaction is triggered by Cpd I species. The O atom above heme-iron was modeled as the oxo atom of Cpd I. , The protonation states of all titratable residues were assigned according to their p K a values calculated by the PROPKA procedure. , Overall, all Glu and Asp residues were deprotonated, while the Arg and Lys residues were protonated. His109, His166, His177, His182, His205, and His 336 were protonated at the epsilon nitrogen, while His254, His262, His264, His316, His344, and His 381 were protonated at the delta nitrogen.…”

My Vision of Electric-Field-Aided Chemistry in 2050

“…In one direction, the charge flows from the donor to the acceptor, i.e., from the HOMO of the diene to the LUMO of the dienophile . In the second, and usually less important direction, the flow is from acceptor to the donor, i.e., from the HOMO of the dienophile to the LUMO of the diene. , As such, there can be in principle a two-way catalysis along the Z axis, as shown by Ramanan et al This is likely to occur in nonpolar cycloaddition reactions. In DA reactions which involve good donor–acceptor pairs, reversing the OEEF encounters a significant energy rise to reach the conversion point .…”

“…In retrospect, the acquired VB thinking turned out to be essential for the developments of the current notions of OEEF and formulating the “reaction axis rule”, which defines the best action of OEEFs on structure and reactivity. − The “reaction axis” is the essential direction along which the OEEF should be applied in order to enhance (or inhibit, if so desired) reaction rates. This rule has served as a conceptual guide and proved to be useful and easily applicable. , As reviewed by Siddiki et al, by now, the task of locating the directions of OEEFs that will minimize the energy barrier for a given reaction system have also been implemented in computational procedures, for example, in refs − . My primary goal in the present Perspective is to outline key principles of using OEEF and to note a few recent experimental studies, which may impact the future of mainstream chemistry and, hence, also my vision for 2050.…”

“…As we shall see next, locating the reaction axis is simple and extremely intuitive. At the same time, it is optional to use one of the computational methods, which have been developed to locate the OEEF direction which will optimize the barrier-lowering effect. − Similarly, there are methods which calculate electric fields from charge distributions. ,, Application of the F Z OEEF along the reaction axis of a given reaction will polarize the TS and increase its dipole moment (μ Z ), as shown in Figure b and Figure a. Flipping the direction of the OEEF along the same axis will decrease the dipole moment of the TS (e.g., see Figure a). The interaction energy of the OEEF, with the polarized dipole moment of the TS or of any species along the reaction axis, is given by eq , as a direct product of the OEEF vector (F Z in units of V/Å) and the corresponding molecular dipole moment vector (μ Z in Debye (D) units) which in turn, involves the due polarization by the OEEF. E int ⁣ false( kcal/mol false) = 4.8 F Z · m Z …”

Electrostatics as a Guiding Principle in Understanding and Designing Enzymes

“…The free energy cost of polarizing the chemical system and the environment must also be included in a complete evaluation of the impact of electrostatic effects on the activation free energy. From a computational point of view, the calculation of electrostatic properties is usually performed using just classical (molecular mechanics, MM) nonpolarizable force fields or in combination with quantum potentials in quantum mechanics/molecular mechanics (QM/MM) schemes . In the first case, polarization is not explicitly included, while in the second case, the polarization of the quantum subsystem is included if an electrostatic embedding scheme is considered .…”