An atomistic understanding of metal transport in the human body is critical to anticipate the side effects of metal-based therapeutics and holds promise for new drugs and drug delivery designs. Human serum transferrin (hTF) is a central part of the transport processes because of its ubiquitous ferrying of physiological Fe(III) and other transition metals to tightly controlled parts of the body. There is an atomistic mechanism for the uptake process with Fe(III), but not for the release process, or for other metals. This study provides initial insight into these processes for a range of transition metals-Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)-through fully atomistic, extensive quantum mechanical/discrete molecular dynamics sampling and provides, to our knowledge, a new technique we developed to calculate relative binding affinities between metal cations and the protein. It identifies protonation of Tyr188 as a trigger for metal release rather than protonation of Lys206 or Lys296. The study identifies the difficulty of metal release from hTF as potentially related to cytotoxicity. Simulations identify a few critical interactions that stabilize the metal binding site in a flexible, nuanced manner.