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Molecular simulations of biomacromolecules that assemble into multimeric complexes remain a challenge due to computationally inaccessible length and time scales. Low-resolution and implicit-solvent coarse-grained modeling approaches using traditional nonbonded interactions (both pairwise and spherically isotropic) have been able to partially address this gap. However, these models may fail to capture the complex anisotropic interactions present at macromolecular interfaces unless higher-order interaction potentials are incorporated at the expense of the computational cost. In this work, we introduce an alternate and systematic approach to represent directional interactions at protein–protein interfaces by using virtual sites restricted to pairwise interactions. We show that virtual site interaction parameters can be optimized within a relative entropy minimization framework by using only information from known statistics between coarse-grained sites. We compare our virtual site models to traditional coarse-grained models using two case studies of multimeric protein assemblies and find that the virtual site models predict pairwise correlations with higher fidelity and, more importantly, assembly behavior that is morphologically consistent with experiments. Our study underscores the importance of anisotropic interaction representations and paves the way for more accurate yet computationally efficient coarse-grained simulations of macromolecular assembly in future research.