Biomolecular structure

Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule of protein, DNA, or RNA, and that is important to its function. The structure of these molecules may be considered at any of several length scales ranging from the level of individual atoms to the relationships among entire protein subunits. This useful distinction among scales is often expressed as a decomposition of molecular structure into four levels: primary, secondary, tertiary, and quaternary. The scaffold for this multiscale organization of the molecule arises at the secondary level, where the fundamental structural elements are the molecule's various hydrogen bonds. This leads to several recognizable domains of protein structure and nucleic acid structure, including such secondary-structure features as alpha helixes and beta sheets for proteins, and hairpin loops, bulges, and internal loops for nucleic acids. The terms primary, secondary, tertiary, and quaternary structure w

Self-Assembly of a Designed Nucleoprotein Architecture through Multimodal Interactions

Henning Paul-Julius Stahlberg, Ling Zhang

The co-self-assembly of proteins and nucleic acids (NAs) produces complex biomolecular machines (e.g., ribosomes and telomerases) that represent some of the most daunting targets for biomolecular design. Despite significant advances in protein and DNA or RNA nanotechnology, the construction of artificial nucleoprotein complexes has largely been limited to cases that rely on the NA-mediated spatial organization of protein units, rather than a cooperative interplay between protein-and NA-mediated interactions that typify natural nucleoprotein assemblies. We report here a structurally well-defined synthetic nucleoprotein assembly that forms through the synergy of three types of intermolecular interactions: Watson-Crick base pairing, NA-protein interactions, and protein-metal coordination. The fine thermodynamic balance between these interactions enables the formation of a crystalline architecture under highly specific conditions.

American Chemical Society (ACS)2018

New Methods for the Integrative Dynamic Modeling of Biomolecular Structures

Sylvain Träger

The true understanding of most cellular functions is only really achievable through the structural determination of their underlying macromolecular assemblies. However, their size, large number of individual components and metastable states make their elucidation by canonical structural biology techniques a vain effort in many situations. As a result, integrative approaches have been in high demand in the recent years. By combining any available data, both computational and experimental, integrative or hybrid modeling strategies have been able to tackle biomolecular structures otherwise intractable by any singular method alone. Over the past decade, structural biology has undergone a significant revolution in the form of cryo-electron microscopy (cryo-EM). With more than 12.000 models of biomolecular structures under its name, cryo-EM however still struggles to approach larger, flexible assemblies at atomic resolution. Instead, such assemblies now routinely fall in an intermediate resolution range, opening new avenues for the development of hybrid approaches primarily based on cryo-EM data. However, the large degrees of flexibility of such assemblies imposes the inclusion of dynamics in the modeling process. Unfortunately, this only makes the already challenging task of defining a scoring function even more difficult. In general, current integrative strategies are thus unable to approach flexible assemblies in a reliable manner. To tackle these issues, two new methods made available to the community are presented in this thesis in addition to their applications to a variety of systems. A new clustering analysis tool, CLoNe, is first introduced. As a significant upgrade to the recent Density Peaks algorithm, we show that CLoNe rivals and outperforms many state-of-the-art algorithms even beyond structural biology. Then, we show how CLoNe is able to extract a variety of information from structural ensembles in general or reduce large ensembles to key components, enabling their successful integration into hybrid modeling approaches. Second, the MaD software is presented. Taking inspiration from traditional computer vision concepts and methods, MaD bypasses the need of a traditional scoring function through the generation of local macromolecular feature descriptors. MaD takes full advantage of the ongoing cryo-EM resolution revolution by integrating local structural information from both cryo-EM data and existing atomic structures. Specifically, MaD is able to predict the quaternary structure of large assemblies regardless of symmetry and conformational variability. Finally, the MaD-CLoNe combination enabled the modeling of molecular chaperones with unprecedented ease. Chaperonins are of crucial importance to ensure proper protein folding and proteostasis. Perturbation of these processes are implicated in neurodegenerative diseases and cancer. In the specific case of the group II chaperonin Mm-Cpn, the use of MaD-CLoNe along with molecular dynamics simulations uncovered new structural models and insight into the chaperonin's functional pathway.

EPFL2021

New Methods for the Integrative Dynamic Modeling of Biomolecular Structures

Sylvain Träger

EPFL2021

Self-Assembly of a Designed Nucleoprotein Architecture through Multimodal Interactions

New Methods for the Integrative Dynamic Modeling of Biomolecular Structures

A technique to find multiple motif ocurrences in a biomolecular sequence

Self-Assembly of a Designed Nucleoprotein Architecture through Multimodal Interactions

New Methods for the Integrative Dynamic Modeling of Biomolecular Structures

A technique to find multiple motif ocurrences in a biomolecular sequence