Development of an Efficient and Accurate Sampling Approach

Biomolecules, such as proteins, DNA, RNA, or signaling molecules, are inherently dynamic molecules, i.e., under the physiological conditions within our body they are constantly moving. While their fundamental structure is clearly defined, their effective shape their so called conformation is continuously fluctuation. The extent and velocity at which this interchange between different conformations takes place is unique for each biomolecular system and strongly depends on the external environment. Knowledge of a biomolecules conformations is crucial for the development of new pharmaceuticals. Computer-aided methods, such as molecular dynamic simulations, allow to model the conformational space of biomolecules by exploring their free energy surface. So called enhanced sampling algorithms facilitate the simulation of dynamic biomolecules at fraction of the computational cost of conventional sampling algorithms. However, this speedup usually comes at the price of a lower precision of the resulting models. Within this project a novel enhanced sampling algorithm will be developed which is both efficient and reliable. Particularly, this methodology will be applied to investigate the dynamic behavior of macrocyclic molecules. Macrocycles are a highly promising class of compounds, which can achieve highly specific interactions and bioavailability. Unfortunately, the synthesis of these molecules is often tedious and financially expensive. Hence, a robust computer-aided optimization before synthesis is of substantial interest in the development of new macrocyclic drugs.

Imagine a world where researchers use computers to explore the hidden secrets of molecules, unraveling their dynamic shapes and behaviors. Our project embarked on a journey into this digital realm, focusing on understanding how molecules change their shapes and interact with their surroundings. At the heart of our project was the exploration of biomolecules, the building blocks of life. These tiny entities hold immense importance, influencing everything from how our bodies function to developing new medicines. However, these molecules are like shape-shifters, adopting different forms in different situations. Understanding these changes is like solving a puzzle crucial for advancing medical discoveries. To unravel these molecular mysteries, we harnessed powerful computer simulations. Think of it as a virtual laboratory, where we used advanced techniques to mimic the behavior of molecules. Our primary goal was to create accurate models of how these molecules change shape - a bit like predicting how a ball of clay morphs when pressed and pulled. As we delved into the project, we encountered challenges that pushed us to innovate. The path was not always straightforward, as the initial method we planned to use faced limitations. But science is about adaptability, so we shifted gears. We embraced a different approach called Hamiltonian Replica Exchange Molecular Dynamics (H-REMD). This method allowed us to peek into the dynamic world of molecules more effectively. Our project had two major parts, each involving exciting collaborations with other experts. In one part, we simulated the behavior of cyclic peptides. By understanding how these molecules change shape, we aimed to design better medicines with fewer side effects. In another part, we worked with specialists who are experts in creating new measurement tools. Together, we developed innovative techniques that provided sharper fundamental insights into how molecules interacted. While the project was successful in many ways, it also faced unexpected turns. Due to personal circumstances, the project concluded earlier than planned. But even in this challenge, we found silver linings. The time working with the host institution and fellow researchers was exceptional, and the project achieved several significant milestones. In a world that is increasingly driven by technology and scientific advancements, our project represents the bridge between computer simulations and real-world applications. By understanding the behavior of molecules in this virtual realm, we open doors to safer drugs, cleaner environments, and healthier lives. Our journey may have faced twists and turns, but it was a testament to the resilience and ingenuity of scientific exploration.