Periodic Reporting for period 1 - FreezeAlz (Theoretical prediction of spectral biomarkers for Alzheimer's disease enabled by highly efficient and adaptable mutli-level response methods)
Período documentado: 2017-07-01 hasta 2019-06-30
Luminescent conjugated oligothiophenes are highly promising candidates for biomarkers for amyloid misfolds and thereby for early-stage detection of neurodegenerative diseases such as Alzheimer’s and Parkinson's disease. The elucidation of the microscopic mechanism and design principles behind these biomarkers requires theoretical assistance. Finding suitable theoretical models that allow sufficiently accurate spectra calculations for such large, dynamic, and complex biomolecular systems is a highly challenging task. There is, hence, a great need for efficient and adaptive theoretical models capable of incorporating the essential factors in spectra calculations of biomolecular systems sufficiently accurately.
The aim of this project is to combine the advantages of several state-of-the-art computational methods and thereby to devise efficient and adaptable methodologies for assisting the interpretation of existing spectra and predicting the performance of new candidates for biomarkers with respect to spectral discrimination of amyloid protein misfolds leading to an improved early-stage detection and more nuanced diagnosis of diseases such as Alzheimer’s and Parkinson’s disease. Currently ca. 6.4 mio EU citizens suffer from dementia and this number is expected to increase significantly within the next decades. Thus, early and nuanced diagnosis of neurodegenerative diseases is of great interest to the European society as such: It will allow a well-tailored medical treatment and thereby increase the patients’ life quality, which will in turn reduce the economic burden.
The aim of this project is to combine the advantages of several state-of-the-art computational methods and thereby to devise efficient and adaptable methodologies for assisting the interpretation of existing spectra and predicting the performance of new candidates for biomarkers with respect to spectral discrimination of amyloid protein misfolds leading to an improved early-stage detection and more nuanced diagnosis of diseases such as Alzheimer’s and Parkinson’s disease. Currently ca. 6.4 mio EU citizens suffer from dementia and this number is expected to increase significantly within the next decades. Thus, early and nuanced diagnosis of neurodegenerative diseases is of great interest to the European society as such: It will allow a well-tailored medical treatment and thereby increase the patients’ life quality, which will in turn reduce the economic burden.
We have:
(i) for the first time, performed large-scale, non-biased molecular dynamics simulations of an amyloid fibril in the presence of luminescent biomarkers. In these simulations, we succeeded in finding a convincing binding site for a family of luminescent oligothiophene biomarkers, which is in agreement with current experimental results. This study has been published in Chem. Commun., 2018, 54, 3030-3033.
(ii) contributed to the development of a novel visualization program VIA-MD (Visual Interactive Analysis of Molecular Dynamics). A particular focus of this development lies on flexible and intuitive analysis of properties of individual molecules or a set of molecules along trajectories. This enables, for instance, the identification of structure-property relationships in dynamic systems. This work has been published in Workshop on Molecular Graphics and Visual Analysis of Molecular Data, The Eurographics Association, 2018, edited by Jan Byska, Michael Krone, and Björn Sommer (https://diglib.eg.org/handle/10.2312/molva20181102).
(iii) established a protocol for the calculation of vibrationally broadened optical spectra from truly anharmonic wave functions in reduced vibrational space. This protocol has proven very promising for oligothiophenes, which are the backbone of the biomarkers of interest. We are currently preparing a peer-reviewed publication presenting these results.
(iv) set up a researchers' network for a modular electronic structure program, which is well suited for the method developments in the FreezeAlz action.
(i) for the first time, performed large-scale, non-biased molecular dynamics simulations of an amyloid fibril in the presence of luminescent biomarkers. In these simulations, we succeeded in finding a convincing binding site for a family of luminescent oligothiophene biomarkers, which is in agreement with current experimental results. This study has been published in Chem. Commun., 2018, 54, 3030-3033.
(ii) contributed to the development of a novel visualization program VIA-MD (Visual Interactive Analysis of Molecular Dynamics). A particular focus of this development lies on flexible and intuitive analysis of properties of individual molecules or a set of molecules along trajectories. This enables, for instance, the identification of structure-property relationships in dynamic systems. This work has been published in Workshop on Molecular Graphics and Visual Analysis of Molecular Data, The Eurographics Association, 2018, edited by Jan Byska, Michael Krone, and Björn Sommer (https://diglib.eg.org/handle/10.2312/molva20181102).
(iii) established a protocol for the calculation of vibrationally broadened optical spectra from truly anharmonic wave functions in reduced vibrational space. This protocol has proven very promising for oligothiophenes, which are the backbone of the biomarkers of interest. We are currently preparing a peer-reviewed publication presenting these results.
(iv) set up a researchers' network for a modular electronic structure program, which is well suited for the method developments in the FreezeAlz action.
The proposal of a convincing binding site for the amyloid biomarkers from non-biased simulations is a major step towards reliable simulation of amyloid biomarkers and therefore also towards rational design of improved fluorescent probes. This may become a game changer for more nuanced diagnosis of neurodegenerative diseases and, hence, of large socio-economic interest to the European society. Moreover, our methodological advances go clearly beyond the previous state of the art and will be important for future research, requiring accurate modeling of optical spectra of biomolecular systems. These advances include an intuitive visualization and analysis tool for structure-property relationships in molecular dynamics simulations and a reliable protocol for anharmonic quantum-mechanical calculations of vibrational broadenings, applicable to medium-sized molecules. Both became only available through the FreezeAlz action.