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We experimentally investigate the viability of a variational quantum gate optimization protocol informed by the underlying physical Hamiltonian of fixed-frequency transmon qubits. The utility of the scheme is demonstrated through the successful experimental optimization of two and three qubit quantum gates tailored on the native cross-resonance interaction. The limits of such a strategy are investigated through the optimization of a gate based on Floquet-engineered three-qubit interactions, however parameter drift is identified as a key limiting factor preventing the implementation of such a scheme which the variational optimization protocol is unable to overcome.

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