Periodic Reporting for period 1 - Mel.Photo.Protect (Unraveling the Photoprotecting Mechanism of Melanin - From a Library of Fragments to Simulation of Spectra and Function)
Berichtszeitraum: 2019-09-01 bis 2021-08-31
In our research programme we aim to provide a new view on the photoprotecting function of melanin based on systematic consideration of its disordered, heterogeneous structure. In particular, we want to answer the following pressing questions related with the photoprotecting function: (1) What specific structural elements are responsible for the broad absorption? What are the absorption properties of the aggregates? How do they depend on the number of units, connectivity and redox state of the oligomers? What is the difference between DHI and DHICA-based aggregates? How are the spectral characteristics of the oligomers tuned in the aggregate environment? How do they depend on aggregate size? (2) What is/are the photoprotection mechanism(s)? Are all aggregates equally capable of dissipating the excitation energy, or is there a particular aggregate type responsible for this function? Is there more than one dissipation mechanism? (3) Why do disaggregation and/or oxidation reduce the photoprotecting efficiency? Is this related to chemiexcitation? To answer these questions, we will simulate the photophysical properties of the different aggregates using state-of-the-art theoretical methods, and we will obtain structure-property relationships telling the us the absorption properties and preferred decay mechanism of the different aggregates. The detailed understanding of the photoprotecting function that we want to deliver will provide new principles for the design of PDA-based functional materials and will help us to assess the possible pathogenic role of melanin chemiexcitation.
Starting from the widely accepted structural model of melanin as a heterogeneous material, our proposal is based on the following hypotheses:
• Oligomer aggregation plays a crucial role in the photophysics and has to be accounted for in realistic models
• Melanin photophysical properties do not stem from a particular aggregate but result from different aggregates that may have similar or complementary properties
• A systematic approach covering structural, redox and geometrical diversity is essential for a full understanding of melanin photoprotecting function
Based on these ideas, the specific objectives are:
• O1. Construct a library of DHI and DHICA based aggregates with structural, redox and geometrical diversity
• O2. Simulate the absorption spectra of the aggregates and establish a structure-property relationship
• O3. Simulate the decay mechanisms for different aggregates
Starting from the widely accepted structural model of melanin as a heterogeneous material, our proposal is based on the following hypotheses:
• Oligomer aggregation plays a crucial role in the photophysics and has to be accounted for in realistic models
• Melanin photophysical properties do not stem from a particular aggregate but result from different aggregates that may have similar or complementary properties
• A systematic approach covering structural, redox and geometrical diversity is essential for a full understanding of melanin photoprotecting function
Based on these ideas, the specific objectives are:
• O1. Construct a library of DHI and DHICA based aggregates with structural, redox and geometrical diversity
• O2. Simulate the absorption spectra of the aggregates and establish a structure-property relationship
• O3. Simulate the decay mechanisms for different aggregates
Towards the objective of this action, results have been achieved:
• A virtual library of DHI dimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHICA dimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHI trimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHICA trimers covering different structural, redox and geometric characteristics has been systematically created.
• Part of a virtual library of DHI tetramers covering different structural, redox and geometric characteristics has been systematically created.
• By simulating the absorption spectra of DHI dimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHICA dimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHI trimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHICA trimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
During the period of this project, Jun Wang has delivered one journal publications to date:
• Jun Wang and Lluís Blancafort*, Angewandte Chemie International Edition, 2021, 60, 18800-18809.
He has additional two journal manuscripts about DHICA dimer and DHI trimer to pentamer underway.
• A virtual library of DHI dimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHICA dimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHI trimers covering different structural, redox and geometric characteristics has been systematically created.
• A virtual library of DHICA trimers covering different structural, redox and geometric characteristics has been systematically created.
• Part of a virtual library of DHI tetramers covering different structural, redox and geometric characteristics has been systematically created.
• By simulating the absorption spectra of DHI dimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHICA dimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHI trimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
• By simulating the absorption spectra of DHICA trimer, a structure-property relationship in terms of the aggregate atomic structure has been established.
During the period of this project, Jun Wang has delivered one journal publications to date:
• Jun Wang and Lluís Blancafort*, Angewandte Chemie International Edition, 2021, 60, 18800-18809.
He has additional two journal manuscripts about DHICA dimer and DHI trimer to pentamer underway.
Beyond the current progress, the next step will be MD simulations. We will use the General Atomic Force Field (GAFF) as implemented in Amber. Preliminary calculations on representative dimers shows that this force field describes our molecules correctly except for the rotation along the inter-monomer bond. Therefore, will be the re-parametrization of the GAFF parameters for rotation along these bonds, using corrected BLYP/6-311G** as the benchmark and a genetic algorithm for the parametrization. We will use our modified version of GAFF to simulate two levels of aggregation: protomolecules made of 5 oligomers (A5 aggregates), and subunits made of 30 oligomers (A30 aggregates), to reach a size of ~4 nm. For practical reasons, we will limit ourselves to homo-aggregates where every A5 or A30 system is made of a single oligomer component. We will start the periodic MD simulations with a high temperature phase to provide enough flexibility to reach the most stable aggregate conformation; after that we will lower the temperature to do the simulation under physiological temperature and pressure conditions. For each aggregate we will do two simulations, one in water solution and the other one of the (periodic) aggregate without solvent. The periodic structures aim at modelling the properties of large eumelanosomes. To create the final set of library structures, a cluster analysis of the MD simulations will be done to see if structural averaging is sufficient or more sophisticated sampling is needed. Based on this library, we will calculate the aggregate spectra to identify the contribution of the different aggregates to the spectra and establish structure-property relationships. Finally, we will study the decay mechanisms of the different oligomers of our library embedded in some of the A30 aggregates.
The expected result is in line with one of the main melanin-related challenges identified by the EuMelaNet special interest group of the European society for Pigment Cell Research (ESPCR), 21 the "need to expand the present set of structure-property-function relationships (...) to tailor melanins for specific applications". Our contribution on the role of different aggregates in the photoprotecting function and our derived structure property relationships will be important to understand melanin biological function and broaden the technological use of its synthetic analogues. Although we will not model chemiexcitation itself, our results will be also highly valuable to assess the possible pathogenic role of melanin chemiexcitation in future studies, because excited states must play a key role in this process. Our research will also be a starting point for future studies on other relevant properties such as antioxidant and free radical scavenger activity, generation of reactive oxygen species through photo- or chemiexcitation, bio-adhesion and coating properties, metal ion sequestration, or paramagnetic and semiconducting properties.
The expected result is in line with one of the main melanin-related challenges identified by the EuMelaNet special interest group of the European society for Pigment Cell Research (ESPCR), 21 the "need to expand the present set of structure-property-function relationships (...) to tailor melanins for specific applications". Our contribution on the role of different aggregates in the photoprotecting function and our derived structure property relationships will be important to understand melanin biological function and broaden the technological use of its synthetic analogues. Although we will not model chemiexcitation itself, our results will be also highly valuable to assess the possible pathogenic role of melanin chemiexcitation in future studies, because excited states must play a key role in this process. Our research will also be a starting point for future studies on other relevant properties such as antioxidant and free radical scavenger activity, generation of reactive oxygen species through photo- or chemiexcitation, bio-adhesion and coating properties, metal ion sequestration, or paramagnetic and semiconducting properties.