Integrative modeling core

核心5：整合建模

CORE 5: INTEGRATIVE MODELING CORE SUMMARY We aim to enable Projects and other Cores to perform structure-based discovery and optimization of ligands for viral protein targets. This goal will be achieved by developing and applying our unique integrative modeling toolbox to compute structural models of the target viral systems, based on varied experimental data from other Cores and Projects. The key challenge in obtaining these models is structural heterogeneity of viral proteins, including large variations in secondary structure content and domain orientations as well as small variations in loop and side chain conformations. Accurate, precise, and complete description and characterization of these multiple states is key to understanding and modulating their functions with ligands. We hypothesize that explicit modeling of multiple conformations of viral proteins is especially needed: Viral proteomes may have evolved to exploit the multiplicity of conformations for delivering function more than the proteomes that are not constrained to a small number of short proteins. We will address this challenge in two ways. First, coarse-grained structural models (Aim 1), based on limited information from cryo-electron microscopy, cryo-electron tomography, chemical cross-linking, and footprinting, will provide an essential step to atomic structures; for example, via design of variants suitable for X-ray crystallography and starting models for high-resolution single particle cryo- EM reconstruction. Second, multi-state atomic models of viral proteins that explicitly describe their heterogeneity will be computed based on data from X-ray crystallography (Aim 2), cryo-electron microscopy (Aim 3), and ligand structure-activity relationship (SAR) studies (Aim 4). Our multi-state models will help reveal static, dynamic, and even cryptic binding pockets of viral proteins, which, in turn, will facilitate ligand discovery and optimization. All Cores and Projects will rely on our models.