Calculation of apparent p<i>K</i><sub>a</sub>values of saturated fatty acids with different lengths in DOPC phospholipid bilayers

Škulj, Sanja; Vazdar, Mario

doi:10.1039/c9cp01204d

Cited by 21 publications

(22 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure 1B shows the potentials of mean force (PMFs), that is, free energy profiles, as a function of the distance from bilayer center ΔZCOM in both the charged (PPL + ) and the neutral (PPL 0 ) forms, as well as under the CpHMD environment. PPL + experiences a large barrier of ~12 kcal/mol as it approaches the bilayer center, consistent with other computational work, 55, 92–98 whereas PPL 0 experiences a moderate barrier of ~3 kcal/mol around the POPC headgroups (ΔZCOM of 15–20 Å) where the charge and density of the system maximize. 34, 55 The PPL + and PPL 0 PMFs experience a crossover at ΔZCOM of 12 Å.…”

Section: Resultssupporting

confidence: 89%

“…34, 55 The PPL + and PPL 0 PMFs experience a crossover at ΔZCOM of 12 Å. Consistent with previous computational studies, 92, 95–98 this suggests a permeation path of the least effort (or lowest free energy), that is, entering the bilayer as PPL + but permeating through it as PPL 0 . With CpHMD turned on, PPL was able to adjust its charge state in response to microenvironment.…”

Section: Resultssupporting

confidence: 86%

“…In other words, CpHMD reproduced the lowest free energy path of the combined fixed-ionization-state PMFs, a commonly adopted approach without rigorous validation. 92, 95–98 Note that CpHMD delineated the path at one-half the computational cost.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Yue

Voth

et al. 2019

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Permeability (P m) across biological membranes is of fundamental importance and a key factor in drug absorption, distribution and development. Although the majority of drugs will be charged at some point during oral delivery, our understanding of membrane permeation by charged species is limited. The canonical model assumes that only neutral molecules partition into and passively permeate across membranes, but there is mounting evidence that these processes are also facile for certain charged species. However, it is unknown whether such ionizable permeants dynamically neutralize at the membrane surface or permeate in their charged form. To probe protonationcoupled permeation in atomic detail, we herein apply continuous constant-pH molecular dynamics along with free energy sampling to study the permeation of a weak base propranolol (PPL), and evaluate the impact of including dynamic protonation on P m. The simulations reveal that PPL dynamically neutralizes at the lipid-tail interface, which dramatically influences the permeation free energy landscape and explains why the conventional model overestimates the assigned intrinsic permeability. We demonstrate how fixed-charge-state simulations can account for this effect, and propose a revised model that better describes pH-coupled partitioning and permeation. Our results demonstrate how dynamic changes in protonation state may play a critical role in the permeation of ionizable molecules, including pharmaceuticals and drug-like molecules, thus requiring a revision of the standard picture.

show abstract

Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 86%

See 1 more Smart Citation

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Yue

Voth

et al. 2019

J. Am. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…In the first one, so-called the "FA cycling" model, FAs act as protonophores. Due to the excess of protons in the mitochondrial intermembrane space, FA carboxyl anions are easily protonated and they can flip-flop across the membrane very fast in the neutral form to the matrix [11][12][13] where a proton is subsequently released. After that, UCP2 facilitates the otherwise very slow transfer of the negatively charged fatty acid by a still unknown mechanism back to the intermembrane space and the cycle starts again [1,8,14].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2

Škulj

Brkljača

Kreiter

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Molecular dynamics (MD) simulations of uncoupling proteins (UCP), a class of transmembrane proteins relevant for proton transport across inner mitochondrial membranes, represent a complicated task due to the lack of available structural data. In this work, we use a combination of homology modelling and subsequent microsecond molecular dynamics simulations of UCP2 in the DOPC phospholipid bilayer, starting from the structure of the mitochondrial ATP/ADP carrier (ANT) as a template. We show that this protocol leads to a structure that is impermeable to water, in contrast to MD simulations of UCP2 structures based on the experimental NMR structure. We also show that ATP binding in the UCP2 cavity is tight in the homology modelled structure of UCP2 in agreement with experimental observations. Finally, we corroborate our results with conductance measurements in model membranes, which further suggest that the UCP2 structure modeled from ANT protein possesses additional key functional elements, such as a fatty acid-binding site at the R60 region of the protein, directly related to the proton transport mechanism across inner mitochondrial membranes.

show abstract

“…This fatty acid, in turn, is converted to oleic acid (c9-C18:1) through the Δ9-desaturase enzyme. In addition, it is an essential component of the membrane, secretory, and transporting lipids, having crucial roles in protein palmitoylation and signaling molecules [53][54][55].…”

Section: Fatty Acid Profilementioning

confidence: 99%

Chitosan and cottonseed processing method association on carcass traits and meat quality of feedlot lambs

et al. 2020

View full text Add to dashboard Cite

The objective of this study was to evaluate the effects of the association of cottonseed processing method with chitosan on carcass traits and meat quality of lambs finished in feedlot. Eighty lambs with an average body weight of 20.6 kg, with 04 months of age, were distributed in a completely randomized design, in a 2 x 2 factorial arrangement. The factors were represented by two cottonseed processing method (whole or ground) and two levels of chitosan (0 and 136 mg/kg BW). The association of cottonseed processing method with chitosan in the lamb diet did not affect (P>0.05) carcasses traits. The pH, color, cooking losses, shear force, and proximate composition of meat were also not affected (P>0.05) by the processing method of cottonseed or its association with chitosan in the lamb diets. There was an increase in palmitoleic (c9-C16:1; P = 0.01) and conjugated linoleic (P = 0.02) fatty acids when ground cottonseed was associated with chitosan. Ground cottonseed associated with chitosan increases the concentration of unsaturated fatty acids in the meat of feedlot lambs.

show abstract

Calculation of apparent pK_avalues of saturated fatty acids with different lengths in DOPC phospholipid bilayers

Abstract: Apparent pKa,app values are calculated for saturated fatty acids of different length embedded in a DOPC bilayer.

Cited by 21 publications

References 59 publications

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2

Chitosan and cottonseed processing method association on carcass traits and meat quality of feedlot lambs

Contact Info

Product

Resources

About

Calculation of apparent pKavalues of saturated fatty acids with different lengths in DOPC phospholipid bilayers

Abstract: Apparent pKa,app values are calculated for saturated fatty acids of different length embedded in a DOPC bilayer.

Cited by 21 publications

References 59 publications

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules

Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2

Chitosan and cottonseed processing method association on carcass traits and meat quality of feedlot lambs

Contact Info

Product

Resources

About

Calculation of apparent pK_avalues of saturated fatty acids with different lengths in DOPC phospholipid bilayers