Context <p>Intrinsic, oriented electric fields inside protein active sites, quantified by vibrational Stark effect (VSE) measurements and electrostatic calculations have been implicated in catalytic preorganization, yet their systematic use to program drug–target lifetimes has remained underexplored. We advance a field-first paradigm in which the component of the protein field projected along a dominant reaction coordinate, denoted as <InlineEquation ID="IEq1"> <EquationSource Format="TEX">${E}_{\parallel }$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>E</mi> <mo stretchy="false">‖</mo> </msub> </math></EquationSource> </InlineEquation> (the component of the protein’s electric field along the reaction coordinate), serves as a tunable design variable for off-rate and residence time (τ). Focusing on two mechanistic archetypes proton sharing (Ketosteroid Isomerase, KSI-like) and bond polarization/dissociation (human aldose reductase, hALR2-like) we show that realistic changes in <InlineEquation ID="IEq2"> <EquationSource Format="TEX">${E}_{\parallel }$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>E</mi> <mo stretchy="false">‖</mo> </msub> </math></EquationSource> </InlineEquation> can tilt barriers, alter curvatures, and modulate tunneling, yielding exponential leverage on kinetics. This reframes pharmacodynamic lifetime as an electrostatic, geometry-addressable property, complementary to affinity optimization and accessible through protein mutations or ligand substituents that re-orient local dipoles.</p> Method <p>We developed a predictive, quantum–mechanical framework grounded in analytical solutions to the one-dimensional time-independent Schrödinger equation. Two experimentally validated systems were modeled viz the proton-transfer dynamics in ketosteroid isomerase (KSI) using an asymmetric double-well potential, and carbonyl polarization/dissociation in human aldose reductase (hALR2) using a modified Morse potential. The intrinsic Stark field was incorporated via its projection onto the reaction coordinate (<InlineEquation ID="IEq3"> <EquationSource Format="TEX">${E}_{\parallel }$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>E</mi> <mo stretchy="false">‖</mo> </msub> </math></EquationSource> </InlineEquation>), coupling through molecular dipole and polarizability terms to tilt and reshape the potential energy landscape. The resulting eigenvalues and wavefunctions provided the parameters for a Grote-Hynes-corrected transition-state theory model with explicit quantum tunneling corrections. This approach quantitatively connects field strength to activation barriers, vibrational frequencies, and ultimately the off-rate (<InlineEquation ID="IEq4"> <EquationSource Format="TEX">${k}_{off}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>k</mi> <mrow> <mi mathvariant="italic">off</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>), enabling the prediction of how perturbations via mutagenesis or ligand design alter residence time.</p>

Engineering drug-protein kinetics via intrinsic quantum Stark fields in binding motifs

期刊论文
发表日期：

2025年11月26日

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Moses Udoisoh,
Mujahid Usman Yahuza,
Patience Folashade Olabinri,
Lucky Endas,
Cosmas Chinweuba Nwose

摘要

Context

Intrinsic, oriented electric fields inside protein active sites, quantified by vibrational Stark effect (VSE) measurements and electrostatic calculations have been implicated in catalytic preorganization, yet their systematic use to program drug–target lifetimes has remained underexplored. We advance a field-first paradigm in which the component of the protein field projected along a dominant reaction coordinate, denoted as ${E}_{\parallel }$ $E_{‖}$ (the component of the protein’s electric field along the reaction coordinate), serves as a tunable design variable for off-rate and residence time (τ). Focusing on two mechanistic archetypes proton sharing (Ketosteroid Isomerase, KSI-like) and bond polarization/dissociation (human aldose reductase, hALR2-like) we show that realistic changes in ${E}_{\parallel }$ $E_{‖}$ can tilt barriers, alter curvatures, and modulate tunneling, yielding exponential leverage on kinetics. This reframes pharmacodynamic lifetime as an electrostatic, geometry-addressable property, complementary to affinity optimization and accessible through protein mutations or ligand substituents that re-orient local dipoles.

Method

We developed a predictive, quantum–mechanical framework grounded in analytical solutions to the one-dimensional time-independent Schrödinger equation. Two experimentally validated systems were modeled viz the proton-transfer dynamics in ketosteroid isomerase (KSI) using an asymmetric double-well potential, and carbonyl polarization/dissociation in human aldose reductase (hALR2) using a modified Morse potential. The intrinsic Stark field was incorporated via its projection onto the reaction coordinate ( ${E}_{\parallel }$ $E_{‖}$ ), coupling through molecular dipole and polarizability terms to tilt and reshape the potential energy landscape. The resulting eigenvalues and wavefunctions provided the parameters for a Grote-Hynes-corrected transition-state theory model with explicit quantum tunneling corrections. This approach quantitatively connects field strength to activation barriers, vibrational frequencies, and ultimately the off-rate ( ${k}_{off}$ $k_{off}$ ), enabling the prediction of how perturbations via mutagenesis or ligand design alter residence time.