Supramolecular assembly of protein building blocks: from folding to function

AbstractSeveral phenomena occurring throughout the life of living things start and end with proteins. Various proteins form one complex structure to control detailed reactions. In contrast, one protein forms various structures and implements other biological phenomena depending on the situation. The basic principle that forms these hierarchical structures is protein self-assembly. A single building block is sufficient to create homogeneous structures with complex shapes, such as rings, filaments, or containers. These assemblies are widely used in biology as they enable multivalent binding, ultra-sensitive regulation, and compartmentalization. Moreover, with advances in the computational design of protein folding and protein–protein interfaces, considerable progress has recently been made in the de novo design of protein assemblies. Our review presents a description of the components of supramolecular protein assembly and their application in understanding biological phenomena to therapeutics.

Download Full-text

De novo design of self-assembling helical protein filaments

Science ◽

10.1126/science.aau3775 ◽

2018 ◽

Vol 362 (6415) ◽

pp. 705-709 ◽

Cited By ~ 48

Author(s):

Hao Shen ◽

Jorge A. Fallas ◽

Eric Lynch ◽

William Sheffler ◽

Bradley Parry ◽

...

Keyword(s):

De Novo ◽

Computational Design ◽

Building Blocks ◽

Repeat Units ◽

Self Assembling ◽

Wide Range ◽

Helical Protein ◽

Monomeric Proteins

We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo–electron microscopy structures of six designs are close to the computational design models. The filament building blocks are idealized repeat proteins, and thus the diameter of the filaments can be systematically tuned by varying the number of repeat units. The assembly and disassembly of the filaments can be controlled by engineered anchor and capping units built from monomers lacking one of the interaction surfaces. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials.

Download Full-text

Computational design and experimental verification of a symmetric protein homodimer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1505072112 ◽

2015 ◽

Vol 112 (34) ◽

pp. 10714-10719 ◽

Cited By ~ 25

Author(s):

Yun Mou ◽

Po-Ssu Huang ◽

Fang-Ciao Hsu ◽

Shing-Jong Huang ◽

Stephen L. Mayo

Keyword(s):

Protein Interactions ◽

De Novo ◽

Computational Design ◽

Atomic Level ◽

Protein Interfaces ◽

Unknown Structure ◽

Α Helix ◽

Distinct Features ◽

Novel Protein

Homodimers are the most common type of protein assembly in nature and have distinct features compared with heterodimers and higher order oligomers. Understanding homodimer interactions at the atomic level is critical both for elucidating their biological mechanisms of action and for accurate modeling of complexes of unknown structure. Computation-based design of novel protein–protein interfaces can serve as a bottom-up method to further our understanding of protein interactions. Previous studies have demonstrated that the de novo design of homodimers can be achieved to atomic-level accuracy by β-strand assembly or through metal-mediated interactions. Here, we report the design and experimental characterization of a α-helix–mediated homodimer with C2 symmetry based on a monomeric Drosophila engrailed homeodomain scaffold. A solution NMR structure shows that the homodimer exhibits parallel helical packing similar to the design model. Because the mutations leading to dimer formation resulted in poor thermostability of the system, design success was facilitated by the introduction of independent thermostabilizing mutations into the scaffold. This two-step design approach, function and stabilization, is likely to be generally applicable, especially if the desired scaffold is of low thermostability.

Download Full-text

ROBUSTNESS-STRENGTH PERFORMANCE OF HIERARCHICAL ALPHA-HELICAL PROTEIN FILAMENTS

International Journal of Applied Mechanics ◽

10.1142/s1758825109000058 ◽

2009 ◽

Vol 01 (01) ◽

pp. 85-112 ◽

Cited By ~ 27

Author(s):

ZHAO QIN ◽

STEVEN CRANFORD ◽

THEODOR ACKBAROW ◽

MARKUS J BUEHLER

Keyword(s):

De Novo ◽

Hierarchical Structures ◽

High Strength ◽

Material Design ◽

Building Blocks ◽

Biological Materials ◽

Strength Performance ◽

Synthetic Materials ◽

Helical Protein ◽

Bioinspired Nanomaterials

An abundant trait of biological protein materials are hierarchical nanostructures, ranging through atomistic, molecular to macroscopic scales. By utilizing the recently developed Hierarchical Bell Model, here we show that the use of hierarchical structures leads to an extended physical dimension in the material design space that resolves the conflict between disparate material properties such as strength and robustness, a limitation faced by many synthetic materials. We report materiomics studies in which we combine a large number of alpha-helical elements in all possible hierarchical combinations and measure their performance in the strength-robustness space while keeping the total material use constant. We find that for a large number of constitutive elements, most random structural combinations of elements (> 98%) lead to either high strength or high robustness, reflecting the so-called banana-curve performance in which strength and robustness are mutually exclusive properties. This banana-curve type behavior is common to most engineered materials. In contrast, for few, very specific types of combinations of the elements in hierarchies (< 2%) it is possible to maintain high strength at high robustness levels. This behavior is reminiscent of naturally observed material performance in biological materials, suggesting that the existence of particular hierarchical structures facilitates a fundamental change of the material performance. The results suggest that biological materials may have developed under evolutionary pressure to yield materials with multiple objectives, such as high strength and high robustness, a trait that can be achieved by utilization of hierarchical structures. Our results indicate that both the formation of hierarchies and the assembly of specific hierarchical structures play a crucial role in achieving these mechanical traits. Our findings may enable the development of self-assembled de novo bioinspired nanomaterials based on peptide and protein building blocks.

Download Full-text

Precise assembly of complex beta sheet topologies from de novo designed building blocks

eLife ◽

10.7554/elife.11012 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 10

Author(s):

Indigo Chris King ◽

James Gleixner ◽

Lindsey Doyle ◽

Alexandre Kuzin ◽

John F Hunt ◽

...

Keyword(s):

De Novo ◽

Computational Design ◽

Building Blocks ◽

Beta Sheets ◽

Protein Domain ◽

Beta Sheet ◽

Design Models ◽

Natural Protein ◽

Complex Protein ◽

Alpha Beta

Design of complex alpha-beta protein topologies poses a challenge because of the large number of alternative packing arrangements. A similar challenge presumably limited the emergence of large and complex protein topologies in evolution. Here, we demonstrate that protein topologies with six and seven-stranded beta sheets can be designed by insertion of one de novo designed beta sheet containing protein into another such that the two beta sheets are merged to form a single extended sheet, followed by amino acid sequence optimization at the newly formed strand-strand, strand-helix, and helix-helix interfaces. Crystal structures of two such designs closely match the computational design models. Searches for similar structures in the SCOP protein domain database yield only weak matches with different beta sheet connectivities. A similar beta sheet fusion mechanism may have contributed to the emergence of complex beta sheets during natural protein evolution.

Download Full-text

Nanoparticles and self-organisation: the emergence of hierarchical properties from the nanoparticle soup (i.e., the small is getting bigger). Concluding remarks for Faraday Discussion: Nanoparticle Synthesis and Assembly.

Faraday Discussions ◽

10.1039/c5fd00094g ◽

2015 ◽

Vol 181 ◽

pp. 481-487 ◽

Cited By ~ 2

Author(s):

David J. Schiffrin

Keyword(s):

Self Assembly ◽

Optical Materials ◽

Nanoparticle Synthesis ◽

Hierarchical Structures ◽

Building Blocks ◽

Main Theme ◽

Colloid Science ◽

Wide Range ◽

Properties Of Materials ◽

Discussion Format

Some four years ago, one of the participants in this Discussion (Prof. Nicholas Kotov) predicted that: “within five years we shall see multiple examples of electronic, sensor, optical and other devices utilizing self-assembled superstructures” (N. A. Kotov, J. Mater. Chem., 2011, 21, 16673–16674). Although this prediction came partially to fruition, we have witnessed an unprecedented interest in the properties of materials at the nanoscale. The point highlighted by Kotov, however, was the importance of self-assembly of structures from well characterised building blocks to yield hierarchical structures, hopefully with predictable properties, a concept that is an everyday pursuit of synthetic chemists. This Discussion has brought together researchers from a wide range of disciplines, i.e., colloid science, modelling, nanoparticle synthesis and organisation, magnetic and optical materials, and new imaging methods, within the excellent traditional Faraday Discussion format, to discuss advances in areas relevant to the main theme of the meeting.

Download Full-text

Beyond icosahedral symmetry in packings of proteins in spherical shells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1706825114 ◽

2017 ◽

Vol 114 (34) ◽

pp. 9014-9019 ◽

Cited By ~ 17

Author(s):

Majid Mosayebi ◽

Deborah K. Shoemark ◽

Jordan M. Fletcher ◽

Richard B. Sessions ◽

Noah Linden ◽

...

Keyword(s):

Self Assembly ◽

De Novo ◽

Multiple Scales ◽

Building Blocks ◽

Icosahedral Symmetry ◽

Protein Cages ◽

Natural Systems ◽

Wide Range ◽

Stable Arrangement ◽

Symmetric Structures

The formation of quasi-spherical cages from protein building blocks is a remarkable self-assembly process in many natural systems, where a small number of elementary building blocks are assembled to build a highly symmetric icosahedral cage. In turn, this has inspired synthetic biologists to design de novo protein cages. We use simple models, on multiple scales, to investigate the self-assembly of a spherical cage, focusing on the regularity of the packing of protein-like objects on the surface. Using building blocks, which are able to pack with icosahedral symmetry, we examine how stable these highly symmetric structures are to perturbations that may arise from the interplay between flexibility of the interacting blocks and entropic effects. We find that, in the presence of those perturbations, icosahedral packing is not the most stable arrangement for a wide range of parameters; rather disordered structures are found to be the most stable. Our results suggest that (i) many designed, or even natural, protein cages may not be regular in the presence of those perturbations and (ii) optimizing those flexibilities can be a possible design strategy to obtain regular synthetic cages with full control over their surface properties.

Download Full-text

Effect of structural variability and flexibility of aliphatic diamines on self-assembly of host-guest coordination polymers constructed of copper cyanide networks: Structure study and catalytic activity

10.21203/rs.3.rs-288076/v1 ◽

2021 ◽

Author(s):

Safaa Eldin H. Etaiw ◽

Safaa N. Abdou Nabih Abdou

Keyword(s):

Catalytic Activity ◽

Self Assembly ◽

Complex Structure ◽

Building Blocks ◽

Structure Study ◽

Ambient Conditions ◽

Structural Variability ◽

3D Network ◽

Aliphatic Diamines ◽

Networks Structure

Abstract A new 3D-host-guest supramolecular coordination polymer (SCP); ∞3[(Cu3(CN)3)2.(DAHP)], 1 [1,7-diaminoheptane=.(DAHP)] had been synthesized by self-assembly at ambient conditions. X-ray single crystal diffraction of SCP 1 indicated the formation of two-fold [Cu3(CN)3]2 units containing tetrahedral copper(I) atoms which are arranged in unique way to create 3D-network. The neutral [Cu3(CN)3]2 building blocks create unique complex structure containing the minicycle [Cu2(μ3-CN)2] motif with wide cavities enable to capsulate the long chain DAHP as guest molecule. The topology of 1 had been studied by elemental analysis, IR-spectra and thermogravimetric analyses. The topology of 1 had been compared with the prototype SCP containing different aliphatic diamines which indicated the effect of structural variability and flexibility of aliphatic diamines on the network structure of these SCP. The catalytic and photo-catalytic activity of 1 was studied for mineralization of methylene blue (MB) utilizing H2O2 as an oxidant.

Download Full-text

Bottom-up Chemoenzymatic Synthesis Towards Novel Fluorinated Cellulose-like Materials

10.26434/chemrxiv.11560173 ◽

2020 ◽

Author(s):

Peterson de Andrade ◽

Juan Munoz ◽

Giulia Pergolizzi ◽

Valeria Gabrielli ◽

Sergey Nepogodiev ◽

...

Keyword(s):

Self Assembly ◽

Soft Matter ◽

Water Solubility ◽

Hierarchical Structures ◽

Building Blocks ◽

Chemoenzymatic Synthesis ◽

Cellulose Ii ◽

Fluorinated Building Blocks ◽

A Minor

Understanding the fine details of self-assembly of building blocks into complex hierarchical structures represents a major challenge en route to the design and preparation of soft matter materials with specific properties. Enzymatically-synthesised cellodextrins are known to have limited water solubility beyond DP9, a point at which they self-assemble into particles resembling the anti-parallel cellulose II crystalline packing. We have prepared and characterized a series of site-selectively fluorinated cellodextrins of different degrees of fluorination and substitution patterns by chemoenzymatic synthesis. The structural characterization of these materials at different length scales, combining advanced NMR and microscopy methods, showed that multiply 6-fluorinated cellodextrin chains assembled into particles presenting morphological and crystallinity features that are unprecedented for cellulose-like materials. In contrast, the introduction of a single fluorine atom per cellodextrin chain had a minor impact on materials structure. Our work emphasizes the strength of combining chemoenzymatic synthesis, fluorinated building blocks and advanced NMR and microscopy methods for the thorough characterization of hierarchical structures, leading to the controlled design of new biomaterials with specific properties.

Download Full-text

Hierarchically Engineered Nanostructures from Compositionally Anisotropic Molecular Building Blocks

10.26434/chemrxiv-2022-tn528 ◽

2022 ◽

Author(s):

Ruiqi Liang ◽

Yazhen Xue ◽

Xiaowei Fu ◽

An Le ◽

Qingliang Song ◽

...

Keyword(s):

Block Copolymers ◽

Nanostructured Materials ◽

Self Assembly ◽

Structural Parameters ◽

Hierarchical Structures ◽

Building Blocks ◽

Assembly Process ◽

Multifunctional Materials ◽

Assembly Strategy ◽

Molecular Building Blocks

The inability to synthesize hierarchical structures with independently tailored nanoscale and mesoscale features limits the discovery of next-generation multifunctional materials. We present a programmable molecular self-assembly strategy to craft nanostructured materials with a variety of phase-in-phase hierarchical morphologies. The compositionally anisotropic building blocks employed in the assembly process are formed by multi-component graft block copolymers (GBCPs) containing sequence-defined side chains. The judicious design of various structural parameters in the GBCPs enables broadly tunable compositions, morphologies, and lattice parameters across the nanoscale and mesoscale in the assembled structures. Our strategy introduces new design principles for the efficient creation of complex hierarchical structures and provides a facile synthetic platform to access nanomaterials with multiple precisely integrated functionalities.

Download Full-text

Computational design of a modular protein sense-response system

Science ◽

10.1126/science.aax8780 ◽

2019 ◽

Vol 366 (6468) ◽

pp. 1024-1028 ◽

Cited By ~ 12

Author(s):

Anum A. Glasgow ◽

Yao-Ming Huang ◽

Daniel J. Mandell ◽

Michael Thompson ◽

Ryan Ritterson ◽

...

Keyword(s):

De Novo ◽

Protein Structures ◽

Computational Design ◽

Metabolic Intermediate ◽

Protein Interfaces ◽

Substantial Progress ◽

Valuable Compounds ◽

Protein Sensors ◽

New Protein

Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals.

Download Full-text