scholarly journals Computational design of nanoscale rotational mechanics in de novo protein assemblies

2021 ◽  
Author(s):  
Alexis Courbet ◽  
Jesse P Hansen ◽  
Yang Hsia ◽  
Neville Bethel ◽  
Young-Jun Park ◽  
...  
Keyword(s):  
Protein Design ◽  
Degrees Of Freedom ◽  
De Novo ◽  
Computational Design ◽  
Interface Energy ◽  
Rotational States ◽  
Rotary Machinery ◽  
Rotational Degrees Of Freedom ◽  
Protein Components ◽  
Rotational Mechanics

Natural nanomachines like the F1/F0-ATPase contain protein components that undergo rotation relative to each other. Designing such mechanically constrained nanoscale protein architectures with internal degrees of freedom is an outstanding challenge for computational protein design. Here we explore the de novo construction of protein rotary machinery from designed axle and ring components. Using cryoelectron microscopy, we find that axle-ring systems assemble as designed and populate diverse rotational states depending on symmetry match or mismatch and the designed interface energy landscape. These mechanical systems with internal rotational degrees of freedom are a step towards the systematic design of genetically encodable nanomachines.

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.

ABOVE THRESHOLD IONIZATION OF POLAR NaK MOLECULES DRIVEN BY FEW-CYCLE LASER PULSE

2010 ◽  
Vol 09 (04) ◽  
pp. 785-795 ◽  
Author(s):  
JIE YU ◽  
CHUAN-CUN SHU ◽  
WEN-HUI HU ◽  
SHU-LIN CONG
Keyword(s):  
Laser Pulse ◽  
Degrees Of Freedom ◽  
Rotational Temperature ◽  
Threshold Ionization ◽  
Rotational States ◽  
Above Threshold Ionization ◽  
Rotational Degrees Of Freedom ◽  
Left And Right ◽  
The Right ◽  
Continuum Wave

We investigate theoretically the above-threshold ionization (ATI) of the polar NaK molecule exposed in few-cycle laser field by numerically solving the time-dependent Schrödinger equation including the vibrational and rotational degrees of freedom. The left and right ATI spectra are calculated by integrating the ionization continuum wave function over the left and the right half spheres along the laser polarization. We find that the left and right ATI spectra are asymmetric, and this asymmetry depends strongly on the molecular orientation and the carrier-envelope phase (CEP) of the laser pulse. Moreover, we also perform the calculation for different initially rotational states to study the effect of rotational temperature on the ATI dynamics.

scholarly journals Breakthroughs in computational design methods open up new frontiers for de novo protein engineering

2021 ◽  
Vol 34 ◽  
Author(s):  
Ben A Meinen ◽  
Christopher D Bahl
Keyword(s):  
Protein Engineering ◽  
Chemical Reactions ◽  
Protein Design ◽  
De Novo ◽  
Computational Design ◽  
Design Methods ◽  
Computational Protein Design ◽  
The Past ◽  
New Methods ◽  
De Novo Protein Design

Abstract Proteins catalyze the majority of chemical reactions in organisms, and harnessing this power has long been the focus of the protein engineering field. Computational protein design aims to create new proteins and functions in silico, and in doing so, accelerate the process, reduce costs and enable more sophisticated engineering goals to be accomplished. Challenges that very recently seemed impossible are now within reach thanks to several landmark advances in computational protein design methods. Here, we summarize these new methods, with a particular emphasis on de novo protein design advancements occurring within the past 5 years.

scholarly journals De novo design of a homo-trimeric amantadine-binding protein

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jooyoung Park ◽  
Brinda Selvaraj ◽  
Andrew C McShan ◽  
Scott E Boyken ◽  
Kathy Y Wei ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Design ◽  
Metal Ion ◽  
Structural Changes ◽  
De Novo ◽  
Computational Design ◽  
Solution Nmr ◽  
Hydrogen Bond Networks ◽  
De Novo Protein Design ◽  
Design Calculations

The computational design of a symmetric protein homo-oligomer that binds a symmetry-matched small molecule larger than a metal ion has not yet been achieved. We used de novo protein design to create a homo-trimeric protein that binds the C3 symmetric small molecule drug amantadine with each protein monomer making identical interactions with each face of the small molecule. Solution NMR data show that the protein has regular three-fold symmetry and undergoes localized structural changes upon ligand binding. A high-resolution X-ray structure reveals a close overall match to the design model with the exception of water molecules in the amantadine binding site not included in the Rosetta design calculations, and a neutron structure provides experimental validation of the computationally designed hydrogen-bond networks. Exploration of approaches to generate a small molecule inducible homo-trimerization system based on the design highlight challenges that must be overcome to computationally design such systems.

On the Use of Quantum Thermal Bath in Unimolecular Fragmentation Simulations

2019 ◽  
Author(s):  
Riccardo Spezia ◽  
Hichem Dammak
Keyword(s):  
Degrees Of Freedom ◽  
Molecular Simulations ◽  
Zero Point ◽  
Thermal Bath ◽  
Unimolecular Dissociation ◽  
Point Energy ◽  
Rotational Degrees Of Freedom ◽  
The Difference ◽  
Nuclear Effects

<div> <div> <div> <p>In the present work we have investigated the possibility of using the Quantum Thermal Bath (QTB) method in molecular simulations of unimolecular dissociation processes. Notably, QTB is aimed in introducing quantum nuclear effects with a com- putational time which is basically the same as in newtonian simulations. At this end we have considered the model fragmentation of CH4 for which an analytical function is present in the literature. Moreover, based on the same model a microcanonical algorithm which monitor zero-point energy of products, and eventually modifies tra- jectories, was recently proposed. We have thus compared classical and quantum rate constant with these different models. QTB seems to correctly reproduce some quantum features, in particular the difference between classical and quantum activation energies, making it a promising method to study unimolecular fragmentation of much complex systems with molecular simulations. The role of QTB thermostat on rotational degrees of freedom is also analyzed and discussed. </p> </div> </div> </div>

scholarly journals Bottom-up de novo protein design

2021 ◽  
Vol 18 (3) ◽  
pp. 233-233
Author(s):  
Arunima Singh
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Bottom Up ◽  
De Novo Protein Design

scholarly journals Rational thermostabilisation of four-helix bundle dimeric de novo proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shin Irumagawa ◽  
Kaito Kobayashi ◽  
Yutaka Saito ◽  
Takeshi Miyata ◽  
Mitsuo Umetsu ◽  
...  
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Protein Complexes ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Saturation Mutagenesis ◽  
Helix Bundle ◽  
Stable Mutant ◽  
Four Helix Bundle ◽  
The Stability

AbstractThe stability of proteins is an important factor for industrial and medical applications. Improving protein stability is one of the main subjects in protein engineering. In a previous study, we improved the stability of a four-helix bundle dimeric de novo protein (WA20) by five mutations. The stabilised mutant (H26L/G28S/N34L/V71L/E78L, SUWA) showed an extremely high denaturation midpoint temperature (Tm). Although SUWA is a remarkably hyperstable protein, in protein design and engineering, it is an attractive challenge to rationally explore more stable mutants. In this study, we predicted stabilising mutations of WA20 by in silico saturation mutagenesis and molecular dynamics simulation, and experimentally confirmed three stabilising mutations of WA20 (N22A, N22E, and H86K). The stability of a double mutant (N22A/H86K, rationally optimised WA20, ROWA) was greatly improved compared with WA20 (ΔTm = 10.6 °C). The model structures suggested that N22A enhances the stability of the α-helices and N22E and H86K contribute to salt-bridge formation for protein stabilisation. These mutations were also added to SUWA and improved its Tm. Remarkably, the most stable mutant of SUWA (N22E/H86K, rationally optimised SUWA, ROSA) showed the highest Tm (129.0 °C). These new thermostable mutants will be useful as a component of protein nanobuilding blocks to construct supramolecular protein complexes.

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