We report on broadly based systematic investigations of the modeling components for open heavy-flavor diffusion and energy loss in strongly interacting matter in their application to heavy-flavor observables in high-energy heavy–ion collisions, conducted within an EMMI Rapid Reaction Task Force framework. Initial spectra including cold-nuclear-matter effects, a wide variety of space-time evolution models, heavy-flavor transport coefficients, and hadronization mechanisms are scrutinized in an effort to quantify pertinent uncertainties in the calculations of nuclear modification factors and elliptic flow of open heavy-flavor particles in nuclear collisions. We develop procedures for error assessments and criteria for common model components to improve quantitative estimates for the (low-momentum) heavy-flavor diffusion coefficient as a long-wavelength characteristic of QCD matter as a function of temperature, and for energy loss coefficients of high-momentum heavy-flavor particles.