Chapter 5 Implicit Modeling of Membranes

Grossfield, Alan

doi:10.1016/s1063-5823(08)00005-7

Cited by 19 publications

(29 citation statements)

References 153 publications

(179 reference statements)

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“…Coarse grained and united atom membrane representations map multiple atoms into a single simulated particle, which reduces the simulation particle count and allows for longer simulation timesteps [67, 68]. The particle count can be reduced even further by removing the explicit membrane atoms altogether, replacing them with an implicit membrane model in which the effect of the membrane is applied as a continuum with varying dielectric [69], again enabling longer simulations. Membrane representations that increase the diffusion constant of the lipids [70] by making them shorter and adding an organic solvent to fill the void have also been developed [71], which accelerates the kinetics of insertion processes [72] while preserving the energetics and specificity of a conventional membrane representation at the membrane periphery [73].…”

Section: Membrane Activity Is a Critical Factor In The Biology Of Smamentioning

confidence: 99%

The cellular membrane as a mediator for small molecule interaction with membrane proteins

Mayne

Arcario

Mahinthichaichan

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The cellular membrane constitutes the first element that encounters a wide variety of molecular species to which a cell might be exposed. Hosting a large number of structurally and functionally diverse proteins associated with this key metabolic compartment, the membrane not only directly controls the traffic of various molecules in and out of the cell, it also participates in such diverse and important processes as signal transduction and chemical processing of incoming molecular species. In this article, we present a number of cases where details of interaction of small molecular species such as drugs with the membrane, which are often experimentally inaccessible, have been studied using advanced molecular simulation techniques. We have selected systems in which partitioning of the small molecule with the membrane constitutes a key step for its final biological function, often binding to and interacting with a protein associated with the membrane. These examples demonstrate that membrane partitioning is not only important for the overall distribution of drugs and other small molecules into different compartments of the body, it may also play a key role in determining the efficiency and the mode of interaction of the drug with its target protein.

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Section: Membrane Activity Is a Critical Factor In The Biology Of Smamentioning

confidence: 99%

The cellular membrane as a mediator for small molecule interaction with membrane proteins

Mayne

Arcario

Mahinthichaichan

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Many vital functions are associated with membranes, such as biosynthesis, signaling, transport, communication and energy conversion. Interactions and reciprocal influence of major membrane components, proteins and lipids, define properties of membranes, including their size, thickness, shape, charge, polarity and density 1–4 . In particular, the presence of proteins affects the lipid order, lateral diffusion, surface tension, and lipid curvature 3, 4 .…”

Section: Introductionmentioning

confidence: 99%

Anisotropic Solvent Model of the Lipid Bilayer. 2. Energetics of Insertion of Small Molecules, Peptides, and Proteins in Membranes

Lomize

Pogozheva

Mosberg

2011

J. Chem. Inf. Model.

139

186

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A new computational approach to calculating binding energies and spatial positions of small molecules, peptides and proteins in the lipid bilayer has been developed. The method combines an anisotropic solvent representation of the lipid bilayer and universal solvation model, which predicts transfer energies of molecules from water to an arbitrary medium with defined polarity properties. The universal solvation model accounts for hydrophobic, van der Waals, hydrogen-bonding, and electrostatic solute-solvent interactions. The lipid bilayer is represented as a fluid anisotropic environment described by profiles of dielectric constant (ε), solvatochromic dipolarity parameter (π*), and hydrogen bonding acidity and basicity parameters (α and β). The polarity profiles were calculated using published distributions of quasi-molecular segments of lipids determined by neutron and X-ray scattering for DOPC bilayer and spin-labeling data that define concentration of water in the lipid acyl chain region. The model also accounts for the preferential solvation of charges and polar groups by water and includes the effect of the hydrophobic mismatch for transmembrane proteins. The method was tested on calculations of binding energies and preferential positions in membranes for small-molecules, peptides and peripheral membrane proteins that have been experimentally studied. The new theoretical approach was implemented in a new version (2.0) of our PPM program and applied for the large-scale calculations of spatial positions in membranes of more than 1000 peripheral and integral proteins. The results of calculations are deposited in the updated OPM database (http://opm.phar.umich.edu).

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“…Implicit solvent models enable simulations to reach longer timescales required to investigate biologically-relevant conformational and sequence changes. Instead of using explicit molecules, implicit methods represent the solvent as a continuous medium (24,25), resulting in a 50-100-fold sampling speedup (26). The most detailed implicit model is the Poisson-Boltzmann (PB) equation, which relates electrostatic potential to dielectric properties of the solvent and solute through a second-order partial differential equation (27).…”

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confidence: 99%

Protein structure prediction and design in a biologically-realistic implicit membrane

Alford

Fleming

et al. 2019

Preprint

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Protein design is a powerful tool for elucidating mechanisms of function and engineering new therapeutics and nanotechnologies. While soluble protein design has advanced, membrane protein design remains challenging due to difficulties in modeling the lipid bilayer. In this work, we developed an implicit approach that captures the anisotropic structure, shape of water-filled pores, and nanoscale dimensions of membranes with different lipid compositions. The model improves performance in computational benchmarks against experimental targets including prediction of protein orientations in the bilayer, ∆∆G calculations, native structure discrimination, and native sequence recovery. When applied to de novo protein design, this approach designs sequences with an amino acid distribution near the native amino acid distribution in membrane proteins, overcoming a critical flaw in previous membrane models that were prone to generating leucine-rich designs. Further, the proteins designed in the new membrane model exhibit native-like features including interfacial aromatic side chains, hydrophobic lengths compatible with bilayer thickness, and polar pores. Our method advances high-resolution membrane protein structure prediction and design toward tackling key biological questions and engineering challenges.membrane proteins | lipid composition | energy function | structure prediction | protein design

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Chapter 5 Implicit Modeling of Membranes

Cited by 19 publications

References 153 publications

The cellular membrane as a mediator for small molecule interaction with membrane proteins

The cellular membrane as a mediator for small molecule interaction with membrane proteins

Anisotropic Solvent Model of the Lipid Bilayer. 2. Energetics of Insertion of Small Molecules, Peptides, and Proteins in Membranes

Protein structure prediction and design in a biologically-realistic implicit membrane

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