MHC-Fine: Fine-tuned AlphaFold for precise MHC-peptide complex prediction.

The precise prediction of major histocompatibility complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset consisting of exclusively high-resolution class I MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of class I MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora as well as the AlphaFold multimer model. Our results demonstrate that our fine-tuned model outperforms others in terms of root-mean-square deviation (median value for Cα atoms for peptides is 0.66 Å) and also provides enhanced predicted local distance difference test scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.

SpikeScape: A Tool for Analyzing Structural Diversity in Experimental Structures of the SARS-CoV-2 Spike Glycoprotein.

In this application note, we describe a tool which we developed to help structural biologists who study the SARS-CoV-2 spike glycoprotein. There are more than 500 structures of this protein available in the Protein Data Bank. These structures are available in different flavors: wild type spike, different variants, 2P substitutions, structures with bound antibodies, structures with Receptor Binding Domains (RBD) in closed or open conformation, etc. Understanding differences between these structures could provide insight into how the spike structure changes in different variants or upon interaction with different molecules such as receptors or antibodies. However, inconsistencies among deposited structures, such as different chain or sequence numbering, hamper a straightforward comparison of all structures. The tool described in this note fixes those chain inconsistencies and calculates the distribution of the requested distance between any two atoms across all SARS-CoV-2 spike structures available in the Protein Data Bank (excluding PDB files with only spike fragments such as the RBD), with the option to filter by various selections. The tool provides a histogram and cumulative frequency of the calculated distribution, as the ability to download the results and corresponding PDB IDs.

Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket.

The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we map the free energy landscape for RBD opening and identify interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.

Search and Localization Dynamics of the CRISPR-Cas9 System.

The CRISPR-Cas9 system acts as the prokaryotic immune system and has important applications in gene editing. The protein Cas9 is one of its crucial components. The role of Cas9 is to search for specific target sequences on the DNA and cleave them. In this Letter, we introduce a model of facilitated diffusion for Cas9 and fit its parameters to single-molecule experiments. Our model confirms that Cas9 search for targets by sliding, but shows that its sliding length is rather short. We then investigate how Cas9 explores a long stretch of DNA containing randomly placed targets. We solve this problem by mapping it into the theory of Anderson localization in condensed matter physics. Our theoretical approach rationalizes experimental evidence on the distribution of Cas9 molecules along the DNA.

MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction.

The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset comprised by exclusively high-resolution MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora [13], as well as the AlphaFold multimer model [8]. Our results demonstrate that our fine-tuned model outperforms both in terms of RMSD (median value is 0.65 Å) but also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.