Principles of assembly reveal a periodic table of protein complexes

Structural insights into protein complexes have had a broad impact on our understanding of biological function and evolution. Here we seek a comprehensive understanding of the general principles underlying quaternary structure organisation in protein complexes. To do this, we first examine the fundamental steps by which protein complexes can assemble using experimental and structure-based characterisation of assembly pathways. Most assembly transitions can be classified into three basic types, which can then be used to exhaustively enumerate a large set of possible quaternary structure topologies. These topologies, which include the vast majority of observed protein complex structures, give rise to a natural organisation into a periodic table. Based upon this, we are then able to accurately predict the expected frequencies of quaternary structure topologies, including those not yet observed. Overall, these results have important implications for quaternary structure prediction, modelling and engineering.This work was supported by the Royal Society (S.E.A. and C.V.R.), the Human Frontier Science Program (J.A.M.), the Medical Research Council grant G1000819 (H.H. and C.V.R.) and the Lister Institute for Preventative Medicine (S.A.T.).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa224

Principles of assembly reveal a periodic table of protein complexes.

Structural insights into protein complexes have had a broad impact on our understanding of biological function and evolution. In this work, we sought a comprehensive understanding of the general principles underlying quaternary structure organization in protein complexes. We first examined the fundamental steps by which protein complexes can assemble, using experimental and structure-based characterization of assembly pathways. Most assembly transitions can be classified into three basic types, which can then be used to exhaustively enumerate a large set of possible quaternary structure topologies. These topologies, which include the vast majority of observed protein complex structures, enable a natural organization of protein complexes into a periodic table. On the basis of this table, we can accurately predict the expected frequencies of quaternary structure topologies, including those not yet observed. These results have important implications for quaternary structure prediction, modeling, and engineering.This work was supported by the Royal Society (S.E.A. and C.V.R.), the Human Frontier Science Program (J.A.M.), the Medical Research Council grant G1000819 (H.H. and C.V.R.) and the Lister Institute for Preventative Medicine (S.A.T.).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa224

The analytic nodal diffusion solver ANDES in multigroups for 3D rectangular geometry: Development and performance analysis

In this work we address the development and implementation of the analytic coarse-mesh finite-difference (ACMFD) method in a nodal neutron diffusion solver called ANDES. The first version of the solver is implemented in any number of neutron energy groups, and in 3D Cartesian geometries; thus it mainly addresses PWR and BWR core simulations. The details about the generalization to multigroups and 3D, as well as the implementation of the method are given. The transverse integration procedure is the scheme chosen to extend the ACMFD formulation to multidimensional problems. The role of the transverse leakage treatment in the accuracy of the nodal solutions is analyzed in detail: the involved assumptions, the limitations of the method in terms of nodal width, the alternative approaches to implement the transverse leakage terms in nodal methods – implicit or explicit _, and the error assessment due to transverse integration. A new approach for solving the control rod ‘‘cusping” problem, based on the direct application of the ACMFD method, is also developed and implemented in ANDES. The solver architecture turns ANDES into an user-friendly, modular and easily linkable tool, as required to be integrated into common software platforms for multi-scale and multi-physics simulations. ANDES can be used either as a stand-alone nodal code or as a solver to accelerate the convergence of whole core pin-by-pin code systems. The verification and performance of the solver are demonstrated using both proof-of-principle test cases and well-referenced international benchmarks

Neighborhood-corrected interface discontinuity factors for multi-group pin-by-pin diffusion calculations for LWR

Performing three-dimensional pin-by-pin full core calculations based on an improved solution of the multi-group diffusion equation is an affordable option nowadays to compute accurate local safety parameters for light water reactors. Since a transport approximation is solved, appropriate correction factors, such as interface discontinuity factors, are required to nearly reproduce the fully heterogeneous transport solution. Calculating exact pin-by-pin discontinuity factors requires the knowledge of the heterogeneous neutron flux distribution, which depends on the boundary conditions of the pin-cell as well as the local variables along the nuclear reactor operation. As a consequence, it is impractical to compute them for each possible configuration; however, inaccurate correction factors are one major source of error in core analysis when using multi-group diffusion theory. An alternative to generate accurate pin-by-pin interface discontinuity factors is to build a functional-fitting that allows incorporating the environment dependence in the computed values. This paper suggests a methodology to consider the neighborhood effect based on the Analytic Coarse-Mesh Finite Difference method for the multi-group diffusion equation. It has been applied to both definitions of interface discontinuity factors, the one based on the Generalized Equivalence Theory and the one based on Black-Box Homogenization, and for different few energy groups structures. Conclusions are drawn over the optimal functional-fitting and demonstrative results are obtained with the multi-group pin-by-pin diffusion code COBAYA3 for representative PWR configurations

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Cotranslational protein folding can facilitate rapid formation of functional structures. However, it might also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched towards the C-termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur prior to assembly. Using high-throughput imaging of protein homomers in vivo in E. coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization

Protein complexes are under evolutionary selection to assemble via ordered pathways

Is the order in which proteins assemble into complexes important for biological function? Here, we seek to address this by searching for evidence of evolutionary selection for ordered protein complex assembly. First, we experimentally characterize the assembly pathways of several heteromeric complexes and show that they can be simply predicted from their three-dimensional structures. Then, by mapping gene fusion events identified from fully sequenced genomes onto protein complex assembly pathways, we demonstrate evolutionary selection for conservation of assembly order. Furthermore, using structural and high-throughput interaction data, we show that fusion tends to optimize assembly by simplifying protein complex topologies. Finally, we observe protein structural constraints on the gene order of fusion that impact the potential for fusion to affect assembly. Together, these results reveal the intimate relationships among protein assembly, quaternary structure, and evolution and demonstrate on a genome-wide scale the biological importance of ordered assembly pathways

EUR 22842 – The Sustainable Nuclear Energy Technology Platform

This vision report prepares the launch of the European Technology Platform on Sustainable Nuclear Energy (SNE-TP). It proposes a vision for the short-, medium- and long-term development of nuclear fi ssion energy technologies, with the aim of achieving a sustainable production of nuclear energy, a signifi cant progress in economic performance, and a continuous improvement of safety levels as well as resistance to proliferation. In particular, this document proposes roadmaps for the development and deployment of potentially sustainable nuclear technologies, as well as actions to harmonise Europe’s training and education, whilst renewing its research infrastructures. Public acceptance is also an important issue for the development of nuclear energy. Therefore, research in the fi elds of nuclear installation safety, protection of workers and populations against radiation, management of all types of waste, and governance methodologies with public participation will be promoted. The proposed roadmaps provide the backbone for a strategic research agenda (SRA) to maintain Europe’s leadership in the nuclear energy sector, in both research and industry. By emphasising the key role of nuclear energy within Europe’s energy mix, this document also contributes to the European Commission’s Strategic Energy Technology Plan, by calling on Europe to mobilise the resources needed to fulfi l the vision of sustainable nuclear energy