Projects / Programmes
The influence of intermolecular interactions on the structure of peptides and proteins
| Code |
Science |
Field |
Subfield |
| 1.04.02 |
Natural sciences and mathematics |
Chemistry |
Structural chemistry |
| Code |
Science |
Field |
| P351 |
Natural sciences and mathematics |
Structure chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
intermolecular interactions, hydrophobicity, protein structure, fibrils, intrinsic unordered proteins, coil helix transition, cold denaturation
Researchers (8)
Organisations (2)
Abstract
The project aims to explore intermolecular forces which are responsible to the change in proteins structure and thus initiate the pathway to toxic fibrils, which are common in all neurodegenerative diseases. The native structure of proteins results from a subtle interplay between intra- and intermolecular interactions. These interactions include electrostatic and van der Waals interactions and hydrogen bonds. Any perturbation in those interactions may lead to misfolding and initialization of the protein self-assembly and consequently to the formation of amyloid fibrils that give rise to serious lethal diseases. The mechanisms of misfolding and aggregation of peptides and proteins are poorly understood. Reasons and initiators of conformational changes of peptides and proteins to form pathological aggregates in vivo are also unclear. However, this knowledge is a prerequisite for the rational design of efficient drugs for the inhibition or reversal of protein aggregation. Current research of amyloidosis is focused on the mechanisms of amyloid-fibril formation, investigation of the structures of misfolded proteins and the characterization of the initiators of structural changes and aggregation. The last two research scopes are the focal points of the proposed project, which will be upgraded with the structural studies of intrinsically unstructured protein (IUP, proNGF) and theoretical treatment of coil to helix transition. Protein aggregation is a very complex process characterized by a remarkable polymorphism, where soluble amyloid oligomers, amyloid fibrils and amorphous aggregates are found together as final products). This polymorphism is associated with the existence of multiple independent and competing assembly pathways leading to aggregation. However, not all oligomers are equally harmful, and several amyloidogenic proteins have been shown to form non-toxic oligomers, some of which were efficient as fibrillation inhibitors. The effective determination of these inhibitors depends on the structure of misfolded peptides and proteins. A significant number of proteins known to be involved in protein deposition disorders were now considered to be IUPs. In terms of polymer physics, IUPs undergo the transition from globular ordered to coil disordered conformational state. The apparent disorder of IUPs was identified to be crucial to their functions. Indeed, they may adopt defined but extended structures when bound to ligands, and thus they can adapt to different binding partners and/or different cellular conditions. As such they cannot be easily crystallized and most structural knowledge on IUPs comes from NMR spectroscopy where time averaging represents serious limitation. Therefore, we plan to introduce the vibrational spectroscopy as an alternative method for structural characterization of IUPs. Moreover, by improvement of empirical methods we would like to contribute to the detailed understanding of IUP and the phenomena of cold denaturation.
It is widely recognized that water molecules play an invaluable role in governing the structure, stability, dynamics, and functions of not only proteins but biomolecules in general. However, the exact processes mediated by water (re)structuring near biomolecules and its role in important bioprocesses such as protein folding, protein aggregation and protein misfolding are far from being understood. Understanding the changes in the local network structure and dynamics of water near solutes is critical for puzzling out the subtle mechanisms responsible for numerous significant biological phenomena. Since the effect of hydrophilic and hydrophobic species on the water structure is well known we will address the first part of the proposal on structural properties of water near combined hydrophobic hydrophilic molecules, by analysing vibrational spectra of alcohols and simple amides dissolved in water.
Significance for science
Activities within the proposed project will significantly contribute to the understanding of the effects which initiate the conformational changes in proteins that consequently induse the formations of toxic fibrils. The first part of the proposal is related to hydrophobic effect, which is one of the most fundamental driving forces in molecular biophysics. Despite the intensive research the microscopic picture of hydrophobicity in the presence of polar groups remains an elusive phenomenon. The improvements of the biomolecular force field which should result in proposed experiments allow exploration of molecular properties at increased accuracy over a wide range of biophysical phenomena. Detailed knowledge of the molecular events in protein folding is important for understanding causes of hundreds of diseases including some of the most dreadful disorders like: Alzheimer's and Parkinson's diseases, some types of cancer, type II diabetes, cystic fibrosis, transmissible prion diseases (“mad cow” disease), etc. With development of some neurodegenerative diseases are connected also neurotrophins. In the sixty years following the discovery of NGF and the subsequent other members of the family, their importance has been increasingly growing. However, still many open questions remain, both on their biology and on their role as molecular actors in various pathologies, like neurodegeneration, epilepsy, depression. In particular, there has been growing interest in the role of their precursors: increasing evidences show an active role for them in the biology of neurotrophins, instead of simply being biosynthetic precursors. Moreover, it has been proven that these precursors have characteristics of intrinsically unstructured domains, able to be versatile in the interaction with different partners. The subtle equilibrium regulating the balance between mature neurotrophins and their precursors is tightly regulated through the proteolytic cleavage of furin and/or other proteases. For this reason, it is needed to know the tridimensional structure of proNGF and the molecular interactions descending from its structural arrangement. This project aims therefore in offering new structure-activity-function information to the scientific community, in order to deepen the available knowledge on NGF and proNGF action. This will be pursued with a solid biophysical approach. The focus of the project will be on the recombinant human NGF and proNGF. The novelty of proposed research described in WP3, as compared to other implicit models, consists in analytical derivation of effective model with temperature-dependent potential from the exact, explicit Hamiltonian. The proposed idea is very ambitious and by its essence represents a ground-breaking concept: our implicit water approach and methodology have the potential to replace computationally-expensive explicit water models relevant for describing biopolymer conformations in scientific and technological tasks such as protein engineering and drug design in a wide range of thermodynamic conditions.
Significance for the country
Activities within the proposed project will significantly contribute to the understanding of the effects which initiate the conformational changes in proteins that consequently induse the formations of toxic fibrils. The first part of the proposal is related to hydrophobic effect, which is one of the most fundamental driving forces in molecular biophysics. Despite the intensive research the microscopic picture of hydrophobicity in the presence of polar groups remains an elusive phenomenon. The improvements of the biomolecular force field which should result in proposed experiments allow exploration of molecular properties at increased accuracy over a wide range of biophysical phenomena. Detailed knowledge of the molecular events in protein folding is important for understanding causes of hundreds of diseases including some of the most dreadful disorders like: Alzheimer's and Parkinson's diseases, some types of cancer, type II diabetes, cystic fibrosis, transmissible prion diseases (“mad cow” disease), etc. With development of some neurodegenerative diseases are connected also neurotrophins. In the sixty years following the discovery of NGF and the subsequent other members of the family, their importance has been increasingly growing. However, still many open questions remain, both on their biology and on their role as molecular actors in various pathologies, like neurodegeneration, epilepsy, depression. In particular, there has been growing interest in the role of their precursors: increasing evidences show an active role for them in the biology of neurotrophins, instead of simply being biosynthetic precursors. Moreover, it has been proven that these precursors have characteristics of intrinsically unstructured domains, able to be versatile in the interaction with different partners. The subtle equilibrium regulating the balance between mature neurotrophins and their precursors is tightly regulated through the proteolytic cleavage of furin and/or other proteases. For this reason, it is needed to know the tridimensional structure of proNGF and the molecular interactions descending from its structural arrangement. This project aims therefore in offering new structure-activity-function information to the scientific community, in order to deepen the available knowledge on NGF and proNGF action. This will be pursued with a solid biophysical approach. The focus of the project will be on the recombinant human NGF and proNGF. The novelty of proposed research described in WP3, as compared to other implicit models, consists in analytical derivation of effective model with temperature-dependent potential from the exact, explicit Hamiltonian. The proposed idea is very ambitious and by its essence represents a ground-breaking concept: our implicit water approach and methodology have the potential to replace computationally-expensive explicit water models relevant for describing biopolymer conformations in scientific and technological tasks such as protein engineering and drug design in a wide range of thermodynamic conditions.
