scholarly journals Design of self-assembling transmembrane helical bundles to elucidate principles required for membrane protein folding and ion transport

2017 ◽  
Vol 372 (1726) ◽  
pp. 20160214 ◽  
Author(s):  
Nathan H. Joh ◽  
Gevorg Grigoryan ◽  
Yibing Wu ◽  
William F. DeGrado
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Protein Design ◽  
De Novo ◽  
Cell Signalling ◽  
Membrane Protein Folding ◽  
Cellular Processes ◽  
Membrane Pores ◽  
Self Assembling ◽  
And Function

Ion transporters and channels are able to identify and act on specific substrates among myriads of ions and molecules critical to cellular processes, such as homeostasis, cell signalling, nutrient influx and drug efflux. Recently, we designed Rocker, a minimalist model for Zn 2+ /H + co-transport. The success of this effort suggests that de novo membrane protein design has now come of age so as to serve a key approach towards probing the determinants of membrane protein folding, assembly and function. Here, we review general principles that can be used to design membrane proteins, with particular reference to helical assemblies with transport function. We also provide new functional and NMR data that probe the dynamic mechanism of conduction through Rocker. This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.

scholarly journals Local Bilayer Hydrophobicity Modulates Membrane Protein Stability

2020 ◽  
Author(s):  
Dagan C. Marx ◽  
Karen G. Fleming
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Hydrophobic Effect ◽  
Water Concentration ◽  
Side Chain ◽  
Interfacial Region ◽  
Side Chains ◽  
Free Energies ◽  
Membrane Protein Folding ◽  
And Function

ABSTRACTThrough the insertion of nonpolar side chains into the bilayer, the hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how the changing chemical composition of the bilayer affects the magnitude side chain transfer free energies has historically not been well understood. A particularly challenging region for experimental interrogation is the bilayer interfacial region that is characterized by a steep polarity gradient. In this study we have determined the for nonpolar side chains as a function of bilayer position using a combination of experiment and simulation. We discovered an empirical correlation between the surface area of nonpolar side chain, the transfer free energies, and the local water concentration in the membrane that allows for to be accurately estimated at any location in the bilayer. Using these water-to-bilayer values, we calculated the interface-to-bilayer transfer free energy . We find that the are similar to the “biological”, translocon-based transfer free energies, indicating that the translocon energetically mimics the bilayer interface. Together these findings can be applied to increase the accuracy of computational workflows used to identify and design membrane proteins, as well as bring greater insight into our understanding of how disease-causing mutations affect membrane protein folding and function.

scholarly journals De novo protein design, a retrospective

2020 ◽  
Vol 53 ◽  
Author(s):  
Ivan V. Korendovych ◽  
William F. DeGrado
Keyword(s):  
Membrane Protein ◽  
Protein Design ◽  
First Principles ◽  
Rational Design ◽  
De Novo ◽  
Dynamic Properties ◽  
Protein Structures ◽  
Amino Acid Sequences ◽  
Physical Models ◽  
And Function

Abstract Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

scholarly journals Applications of Single-Molecule Methods to Membrane Protein Folding Studies

2018 ◽  
Vol 430 (4) ◽  
pp. 424-437 ◽  
Author(s):  
Robert E. Jefferson ◽  
Duyoung Min ◽  
Karolina Corin ◽  
Jing Yang Wang ◽  
James U. Bowie
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Single Molecule ◽  
Membrane Protein Folding

scholarly journals In-Situ Observation of Membrane Protein Folding during Cell-Free Expression

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0151051 ◽  
Author(s):  
Axel Baumann ◽  
Silke Kerruth ◽  
Jörg Fitter ◽  
Georg Büldt ◽  
Joachim Heberle ◽  
...  
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Free Expression ◽  
In Situ Observation ◽  
Membrane Protein Folding

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

2019 ◽  
Author(s):  
Rebecca F. Alford ◽  
Patrick J. Fleming ◽  
Karen G. Fleming ◽  
Jeffrey J. Gray
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Structure Prediction ◽  
Protein Design ◽  
Structure Prediction ◽  
De Novo ◽  
Computational Design ◽  
Amino Acid Distribution

ABSTRACTProtein 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 bench-marks against experimental targets including prediction of protein orientations in the bilayer, ΔΔG calculations, native structure dis-crimination, 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.Significance StatementMembrane proteins participate in many life processes including transport, signaling, and catalysis. They constitute over 30% of all proteins and are targets for over 60% of pharmaceuticals. Computational design tools for membrane proteins will transform the interrogation of basic science questions such as membrane protein thermodynamics and the pipeline for engineering new therapeutics and nanotechnologies. Existing tools are either too expensive to compute or rely on manual design strategies. In this work, we developed a fast and accurate method for membrane protein design. The tool is available to the public and will accelerate the experimental design pipeline for membrane proteins.

Membrane Protein Folding and Stability

2021 ◽  
pp. 137-160
Author(s):  
Stephen H. White ◽  
Gunnar von Heijne ◽  
Donald M. Engelman
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Membrane Protein Folding

scholarly journals Protein designer David Baker: I like doing things that seem like magic

2020 ◽  
Vol 7 (8) ◽  
pp. 1410-1412
Author(s):  
Weijie Zhao ◽  
Chu Wang
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Protein Structures ◽  
Computational Prediction ◽  
Biological Functions ◽  
Personal Experiences ◽  
De Novo Protein Design ◽  
And Function ◽  
The University ◽  
Opening Up

Abstract Search ‘de novo protein design’ on Google and you will find the name David Baker in all results of the first page. Professor David Baker at the University of Washington and other scientists are opening up a new world of fantastic proteins. Protein is the direct executor of most biological functions and its structure and function are fully determined by its primary sequence. Baker's group developed the Rosetta software suite that enabled the computational prediction and design of protein structures. Being able to design proteins from scratch means being able to design executors for diverse purposes and benefit society in multiple ways. Recently, NSR interviewed Prof. Baker on this fast-developing field and his personal experiences.

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