Investigating the Role of Sampling on Absolute Ligand Binding Free Energy Predictions

Diplôme Thèse Investigating the Role of Sampling on Absolute Ligand Binding Free Energy Predictions eng 2024-10-04 2024-10-22 author Karrenbrock Maurice 0000-0003-1280-8464 947953 director Gervasio Francesco Luigi 0000-0003-4831-5039 931636 Section des sciences pharmaceutiques (FARMA) 10.13097/archive-ouverte/unige:181900 urn:nbn:ch:unige-1819004 Sc. Vie - Pharma. 311 <p>Computational techniques are increasingly being used to speed up the search for new drugs in the early stages of the drug discovery process. The accurate calculation of protein-ligand binding affinity is a crucial part in this process, but remains a major challenge for complex systems. This is particularly true in cases where the correct binding pose is not known, or where unknown slow degrees of freedom influence the estimated values. Given the ever growing need of in silico methods that provide accurate estimates of the binding free energy of small molecules, during my PhD, I worked on two complementary approaches that can address different difficulties associated with the calculation of ligand binding free energies. The first method is based on non-equilibrium alchemical transformations, while the second one is based on free energy calculations along geometrical descriptors called collective variables.</p> <p>The two approaches are complementary with distinct strengths and weaknesses. My contribution has been to develop certain aspects of them so they can be applied in cases where other methods fail. In particular, the two methods reduce the dependency on the initial configuration of the system and can sample thoroughly the relevant slow degrees of freedom of the system without getting stuck in metastable states due to under-sampled slow degrees of freedom. At the same time, while developing the algorithms, I tried to keep their applicability as general, automatable, and system-agnostic as possible</p> Dewey 615 31 Section des sciences pharmaceutiques 17 false 1387 Gervasio Francesco 1039 091d437d-6414-4f5a-bf1b-ce3d23c9e673 Thesis Public phd_thesis_MKarrenbrock-1.pdf 45631340 application/pdf 5691778cc8ee9dc1682bfa52b8a1b18d76f135fe3ba3a60a3dadb018a5f5fc09 cd1d3430-bafc-42bb-8637-d7e0f7b4e489 Imprimatur Public imprimatur.pdf 173740 application/pdf c4c78e167bd1d8d8d222d9e6dc8c0a3d63d4b30eb175fdd1d4fb7abbf553ce98 openAccess Faculté des sciences / Section des sciences pharmaceutiques

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