<p>Proteins are significant components of living cells. They perform a diverse range of biological functions such as cell shape and metabolism. The functions of proteins are determined by their three-dimensional structures. Cryogenic-electron microscopy (cryo-EM) is a technology known for determining the structure of large macromolecular structures including protein complexes. When individual atomic protein structures are available, a critical task in structure modeling is fitting the individual structures into the cryo-EM density map.</p> <p>In my research, I report a new computational method, MarkovFit, which is a machine learning-based method that performs simultaneous rigid fitting of the atomic structures of individual proteins into cryo-EM maps of medium to low resolution to model the three-dimensional structure of protein complexes. MarkovFit uses Markov random field (MRF), which allows probabilistic evaluation of fitted models. MarkovFit starts by searching the conformational space using FFT for potential poses of protein structures, computes scores which quantify the goodness-of-fit between each individual protein and the cryo-EM map, and the interactions between the proteins. Afterwards, proteins and their interactions are represented using a MRF graph. MRF nodes use a belief propagation algorithm to exchange information, and the best conformations are then extracted and refined using two structural refinement methods. </p> <p>The performance of MarkovFit was tested on three datasets; a dataset of simulated cryo-EM maps at resolution 10 Å, a dataset of high-resolution experimentally-determined cryo-EM maps, and a dataset of experimentally-determined cryo-EM maps of medium to low resolution. In addition to that, the performance of MarkovFit was compared to two state-of-the-art methods on their datasets. Lastly, MarkovFit modeled the protein complexes from the individual protein atomic models generated by AlphaFold, an AI-based model developed by DeepMind for predicting the 3D structure of proteins from their amino acid sequences.</p>