This thesis introduces the concept of "physics-based inverse design", working on the notion that the physical driving forces governing functionality are inherently encoded in independently... Show moreThis thesis introduces the concept of "physics-based inverse design", working on the notion that the physical driving forces governing functionality are inherently encoded in independently parameterized energy functions, which can be resolved through the use of inverse design strategies.The thesis describes the development of EVO-MD, a Python-based implementation of the physics-based inverse design concept. EVO-MD is capable of automatically setting-up, performing, and analyzing molecular dynamics simulations, allowing for the evolutionary optimization of complex and dynamic features in peptides. Examples of such applications include the optimization of lipid composition and curvature sensors, and the development of peptides with antiviral properties. Show less
Gorostiola González, M.; Broek, R.L. van den; Braun, T.G.M.; Chatzopoulou Chatzi A.; Jespers, W.; IJzerman, A.P.; ... ; Westen, G.J.P. van 2023
Proteochemometric (PCM) modelling is a powerful computational drug discovery tool used in bioactivity prediction of potential drug candidates relying on both chemical and protein information. In... Show moreProteochemometric (PCM) modelling is a powerful computational drug discovery tool used in bioactivity prediction of potential drug candidates relying on both chemical and protein information. In PCM features are computed to describe small molecules and proteins, which directly impact the quality of the predictive models. State-of-the-art protein descriptors, however, are calculated from the protein sequence and neglect the dynamic nature of proteins. This dynamic nature can be computationally simulated with molecular dynamics (MD). Here, novel 3D dynamic protein descriptors (3DDPDs) were designed to be applied in bioactivity prediction tasks with PCM models. As a test case, publicly available G protein-coupled receptor (GPCR) MD data from GPCRmd was used. GPCRs are membrane-bound proteins, which are activated by hormones and neurotransmitters, and constitute an important target family for drug discovery. GPCRs exist in different conformational states that allow the transmission of diverse signals and that can be modified by ligand interactions, among other factors. To translate the MD-encoded protein dynamics two types of 3DDPDs were considered: one-hot encoded residue-specific (rs) and embedding-like protein-specific (ps) 3DDPDs. The descriptors were developed by calculating distributions of trajectory coordinates and partial charges, applying dimensionality reduction, and subsequently condensing them into vectors per residue or protein, respectively. 3DDPDs were benchmarked on several PCM tasks against state-of-the-art non-dynamic protein descriptors. Our rs- and ps3DDPDs outperformed non-dynamic descriptors in regression tasks using a temporal split and showed comparable performance with a random split and in all classification tasks. Combinations of non-dynamic descriptors with 3DDPDs did not result in increased performance. Finally, the power of 3DDPDs to capture dynamic fluctuations in mutant GPCRs was explored. The results presented here show the potential of including protein dynamic information on machine learning tasks, specifically bioactivity prediction, and open opportunities for applications in drug discovery, including oncology. Show less
The long-held desire - to link structure directly to function and to explain molecular mechanisms based on basic chemical or physical principles - is finally coming closer, satisfying not only our... Show moreThe long-held desire - to link structure directly to function and to explain molecular mechanisms based on basic chemical or physical principles - is finally coming closer, satisfying not only our scientific curiosity but also offering new solutions to the many challenges in the field of health, energy and sustainability. This thesis aims to understand the mechanisms of the largest and most efficient antenna complex in photosynthetic bacteria, the chlorosome, at the molecular level. By linking classical methods for the description of molecular motions to quantum models for electronic movements, and comparison with experimental data, I was able to unambiguously determine the molecular structure of chlorosomes. Moreover, this hybrid approach provided new and unique insight into how these antennae encode robust and efficient functions in structure and structural dynamics. This elucidates the origin of their photosynthetic efficiency, which can be useful for the design of new generations of solar cells. Furthermore, we gain unique insight into the versatile ways in which nature encodes its functions: not only in DNA, but also in the way molecules arrange themselves in a larger aggregate, and the dynamics that results from it. Show less
To be able to perform Molecular Dynamics (MD) simulations of proteins, a model is needed to describe the interactions between the atoms witin the protein. The interactions between a metal-ion, in... Show moreTo be able to perform Molecular Dynamics (MD) simulations of proteins, a model is needed to describe the interactions between the atoms witin the protein. The interactions between a metal-ion, in this case copper, and a ligand can vary strongly so that a standard set can not be used. This thesis describes the development of a non-bonded and a covalently bonded force field for the copper-site by using an empirically resp. quantum chemically derived charge distribution. The force fields were applied on several instances. 1) It appears that the possible involvement of a mobile loop after substrate binding to the copper-containing quercetinase may help keeping the substrate in place. 2) It turns out that the thermodynamic integration method only allows qualitative predictions of the variation in redox potential observed for azurin variants. 3) The dynamics of the hydrophobic core of azurin variants were analysed in light of previous time dependent phosphorescence experiments. They stress the importance of charge and dipole variations of the surroundings of the tryptophane in the structure for its phosphorescence properties. 4) Finally MD simulations show that a loop, carrying an engineered cysteine, is able to undergo a large conformational change enabling to co-ordinate the copper site of azurin. Show less
Rodziewicz, P.; Melikova, S.M.; Rutkowski, K.S.; Buda, F. 2005
