Protonation and orientation: a computational approach to cocaine diffusion through a model membrane

Oung, Sangwar Wadtey; Kremer, Nora; Amara, Safa Ben; Zaidi, Ali; Koslowski, Thorsten

doi:10.1039/d2cp01140a

Cited by 4 publications

(5 citation statements)

References 49 publications

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“…In addition, significant regions of each neutral PMF are below zero, corresponding to higher equilibrium probability in the POPC bilayer than in the aqueous phase. This property of neutral organic small molecules in lipid membranes has been observed before, for instance, in the case of propranolol (PPL), 28,59,88 cocaine, 37 short-chain alcohols, 88 and ibuprofen. 30 The protonated states of nicotine (Figure 2A, black and red) and state of varenicline (Figure 2B, black) face significant barriers against permeation, as would be expected considering the more stable solvation of a charged species in the aqueous phase compared to the hydrophobic interior of a membrane, especially in the context of an additive force field.…”

Section: Potential Of Mean Force and Position-dependent Diffusivitysupporting

confidence: 67%

“…36 A radically different physical picture from pH-partitioning is obtained if it is assumed that the interconversion protonation/ The Journal of Physical Chemistry B deprotonation rates are much faster than the spatial diffusion of the permeant. In this case, the permeating molecule is expected to diffuse along an effective pH-dependent potential corresponding to a Boltzmann-weighted average of the individual W s (z) of each ionization state s. 37,38 The effective average potential can then be used within the ISD framework to calculate the effective permeability via eq 1. This is the approach used by Oung et al 37 to model membrane permeation of cocaine.…”

Section: Introductionmentioning

confidence: 99%

“…In this case, the permeating molecule is expected to diffuse along an effective pH-dependent potential corresponding to a Boltzmann-weighted average of the individual W s ( z ) of each ionization state s . , The effective average potential can then be used within the ISD framework to calculate the effective permeability via eq . This is the approach used by Oung et al to model membrane permeation of cocaine. Assuming fast interconversion rates on the time scale of an MD simulation is formally equivalent to the results obtained by employing constant-pH MD (CpHMD) simulations, − which impose equilibrium partition among all of the ionization states for every configuration of a system .…”

Section: Introductionmentioning

confidence: 99%

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How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

Harris,

Chipot,

Roux

2024

J. Phys. Chem. B

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According to the pH-partition hypothesis, the aqueous solution adjacent to a membrane is a mixture of the ionization states of the permeating molecule at fixed Henderson− Hasselbalch concentrations, such that each state passes through the membrane in parallel with its own specific permeability. An alternative view, based on the assumption that the rate of switching ionization states is instantaneous, represents the permeation of ionizable molecules via an effective Boltzmann-weighted average potential (BWAP). Such an assumption is used in constant-pH molecular dynamics simulations. The inhomogeneous solubilitydiffusion framework can be used to compute the pH-dependent membrane permeability for each of these two limiting treatments. With biased WTM-eABF molecular dynamics simulations, we computed the potential of mean force and diffusivity of each ionization state of two weakly basic small molecules: nicotine, an addictive drug, and varenicline, a therapeutic for treating nicotine addiction. At pH = 7, the BWAP effective permeability is greater than that determined by pH-partitioning by a factor of 2.5 for nicotine and 5 for varenicline. To assess the importance of ionization kinetics, we present a Smoluchowski master equation that includes explicitly the protonation and deprotonation processes coupled with the diffusive motion across the membrane. At pH = 7, the increase in permeability due to the explicit ionization kinetics is negligible for both nicotine and varenicline. This finding is reaffirmed by combined Brownian dynamics and Markov state model simulations for estimating the permeability of nicotine while allowing changes in its ionization state. We conclude that for these molecules the pH-partition hypothesis correctly captures the physics of the permeation process. The small free energy barriers for the permeation of nicotine and varenicline in their deprotonated neutral forms play a crucial role in establishing the validity of the pH-partitioning mechanism. Essentially, BWAP fails because ionization kinetics are too slow on the time scale of membrane crossing to affect the permeation of small ionizable molecules such as nicotine and varenicline. For the singly protonated state of nicotine, the computational results agree well with experimental measurements (P 1 = 1.29 × 10 −7 cm/s), but the agreement for neutral (P 0 = 6.12 cm/s) and doubly protonated nicotine (P 2 = 3.70 × 10 −13 cm/s) is slightly worse, likely due to factors associated with the aqueous boundary layer (neutral form) or leaks through paracellular pathways (doubly protonated form).

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Section: Potential Of Mean Force and Position-dependent Diffusivitysupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

Harris,

Chipot,

Roux

2024

J. Phys. Chem. B

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“…As has been discussed in Modulation of the Membrane Permeability by Titratable Groups, however, the commonly accepted view of passive permeation of titratable species is that of a neutral substrate traversing the hydrophobic interior of the membrane . Though the rate of permeation is not necessarily on par with the slow proton kinetics of the permeantand, in fact, it seldom is, a hybrid model has been suggested, , whereby the PMF underlying translocation reflects a predominant ionized form of the substrate in the aqueous medium, and a predominant neutral form in the lipid phase (see Figure ).…”

Section: Application To the Membrane Permeability To Ibuprofenmentioning

confidence: 99%

Predictions from First-Principles of Membrane Permeability to Small Molecules: How Useful Are They in Practice?

Chipot

2023

J. Chem. Inf. Model.

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Predicting from first-principles the rate of passive permeation of small molecules across the biological membrane represents a promising strategy for screening lead compounds upstream in the drug-discovery and development pipeline. One popular avenue for the estimation of permeation rates rests on computer simulations in conjunction with the inhomogeneous solubility–diffusion model, which requires the determination of the free-energy change and position-dependent diffusivity of the substrate along the translocation pathway through the lipid bilayer. In this Perspective, we will clarify the physical meaning of the membrane permeability inferred from such computer simulations, and how theoretical predictions actually relate to what is commonly measured experimentally. We will also examine why these calculations remain both technically challenging and overly computationally expensive, which has hitherto precluded their routine use in nonacademic settings. We finally synopsize possible research directions to meet these challenges, increase the predictive power of physics-based rates of passive permeation, and, by ricochet, improve their practical usefulness.

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“…Recently, alternative numerical schemes have been developed for solving diffusion equations with coordinate-dependent chemical potential. Koslowski and coworkers applied a closely related scheme to numerically solve the diffusion equation for cocaine diffusion across the membrane with a Monte Carlo-type approach (23). Ghysels et al studied oxygen transport across the membranes by solving the Smoluchowski equation, where the potential of mean force was calculated by molecular dynamics simulation in conjunction with biased sampling (24).…”

Section: Numerical Solving Of Diffusion Equation With Coordinate-depe...mentioning

confidence: 99%

Microkinetics of Lidocaine and Bupivacaine Transfer across Myelinated Nerve Fibre

Smrkolj

Pregeljc

Kavcic

et al. 2022

Preprint

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Background The present study aimed to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on the experimental dimensions of a typical nerve and experimental octanol/water partition coefficients. Methods We started our compilation of experimental data with a numerical solution of the diffusion equation of transfer of lidocaine and bupivacaine across the axon membrane at the region of the node of Ranvier (axolemma) and across the Schwann cell. By including the coordinate-dependent chemical potential, the difference between the aqueous and lipid environments of the neuron was simulated. In the second step, permeation rates calculated using the diffusion equation were applied to solve a system of four ordinary differential equations. This approach allowed us to simulate the cell environment for longer, enabling us to compare our model to the pharmacokinetic properties (time to onset and duration of action) of local anaesthetics found in the literature. The behaviour of local anaesthetics under physiological conditions and in the case of local acidosis was also simulated. Results We demonstrated that local anaesthetics cross the axolemma on a sub-microsecond time scale. Time to onset, controlled by diffusion from epineurium to an axon with a typical distance of 500 µm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. Calculated half-time, which is a measure of the duration of action, was 41min and 328 min for lidocaine and bupivacaine, respectively. Conclusions Duration of action is controlled by the storage capacity of lipophilic compartments around the axon that are higher for bupivacaine and lower in the case of local acidosis. For the latter case, the literature, including textbooks, provides an incorrect interpretation that protonated species cannot penetrate the membrane.

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Protonation and orientation: a computational approach to cocaine diffusion through a model membrane

Abstract: We study the diffusion of cocaine through a DMPC lipid bilayer as an example of a protonable, amphiphilic molecule passing a biological membrane. Using classical molecular dynamics simulations, the free...

Cited by 4 publications

References 49 publications

How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

Predictions from First-Principles of Membrane Permeability to Small Molecules: How Useful Are They in Practice?

Microkinetics of Lidocaine and Bupivacaine Transfer across Myelinated Nerve Fibre

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