Material design using Martini:Accelerating discovery through coarse-grained simulations

Advanced materials are a fundamental aspect of our modern everyday life. From batteries to solar cells and vaccines, the development of new functional materials is key in addressing societal challenges of the 21st century, yet the development process is often slow and expensive. Computational studies can accelerate this process but to fully realize their potential, they require infrastructure in the form of software, protocols, and benchmarks of these protocols. The thesis at hand starts with an in-depth review of the current usage of the Martini coarse-grained (CG) simulation technique in the field of material science. Subsequently, it lays the groundwork to realize the next stage of the rational design of complex heterogeneous materials utilizing Martini CG simulations. In particular, two newly developed software tools are introduced to facilitate high-throughput workflows. The open-source Vermouth python library and Polyply software suite efficiently automate the simulation setup of complex materials and sharing of simulation input parameters. Subsequently, two libraries of simulation parameters for carbohydrates and synthetic polymers are presented and benchmarked. Finally, a proof-of-concept method is presented to incorporate pH effects in Martini simulations. This protocol allows to study the response of materials to changes in pH, which is a common mechanism to functionalize materials. Taken together these developments enable the simulation of highly complex materials and offer a comprehensive collection of Martini (bio)-polymer parameters

Investigation of Heterogeneous Proteins and Protein Complexes with Native Ion Mobility-Mass Spectrometry and Theory

Native ion mobility-mass spectrometry (IM-MS) offers many advantages for the study of biomolecules and their complexes. High mass accuracy and sensitivity enable unambiguous determination of complex stoichiometries with respect to subunit composition as well as bound ligands. Ion mobility spectrometry adds an additional dimension of separation and can provide some structural information. Native IM-MS experiments are also fast with minimal sample requirements. Because of these reasons, native IM-MS has become an important tool in structural biology, able to investigate challenging samples that may not be amenable to study by other techniques. However, there are still some major challenges for using native IM-MS in the study of biomolecules. Heterogeneity—arising from the presence of multiple conformations, subunit compositions, ligands and small molecules, for example—results in complicated native mass spectra that can be difficult or even impossible to deconvolute and interpret. Characterizing the heterogeneity of these samples is desirable, as reports of lipids, small drugs, and metals being important for physiological structure and function continue to accumulate. Additionally, interpretation of structural information from IM data has remained largely qualitative, and more fundamental questions about this technique persist, including detailed understanding of the nature of gas-phase protein structure and behavior and how it might differ from solution-phase. Investigation into this aspect is required to make structural interpretation from native IM-MS data quantitative. In the first half of this dissertation, strategies to overcome the challenges of heterogeneity are explored, and computational methods are developed to solve the quantitation problem. With these methods, key features of gas-phase protein ion compaction are revealed, allowing more informed interpretation of structural details from this technique. The second half of this dissertation illustrates the wealth of information that can be accessed for challenging, heterogeneous biomolecules in native IM-MS experiments upon application of these computational methods. With results from both experiment and computation, oligomeric states of the membrane pore-forming protein toxin Cytolysin A are identified, and the composition and topology of multimeric β-crystallin protein complexes, which are implicated in cataract formation, are characterized. This dissertation includes previously published and unpublished co-authored material