||The formation of calcium phosphate (Ca-P) precipitates in a simulated physiological environment and in the living body plays a key role in evaluating the bioactivity and osteoconduction of biomaterials because Ca-P, hydroxyapatite (HA) or octacalcium phosphate (OCP) has a composition and structure similar to that of the minerals in human hard tissue. Proteins in physiological environments have a great effect on the Ca-P formation and play an important role in the biomineralization. However, given the diversity and complex structure of proteins, the mechanism of protein regulating Ca-P precipitates is still unclear and the interactions between proteins and Ca-P at atomic or molecular level are not well understood. The objectives of this study include: (1) Experimentally investigate the change of morphology, size, structure, phase, crystallinity and precipitating speed of Ca-P precipitates formed on three types of bioceramics under modulation of acidic bovine serum albumin (BSA) and basic lysozyme (LSZ) in vitro; and evaluate the protein effects on Ca-P precipitates in vivo. (2) Thermodynamic and kinetic analysis of the protein effects on the Ca-P precipitation in simulated body fluid (SBF). (3) Molecular dynamics (MD) simulation of the protein effect on the interfacial energy between HA surfaces and aqueous solutions. (4) MD simulation of the behavior of the acidic/basic protein adsorption on the crystallographic planes of Ca-P. (5) MD simulation of interaction between the acidic/basic proteins and Ca-P crystals or ions. Three types of bioceramics, HA, Biphasic calcium phosphate (BCP) and β-tricalcium phosphate (β-TCP) were immersed in SBF with BSA or LSZ for in vitro study; and also the bioceramic specimens were implanted into the body of a dog for in vivo study. The results showed BSA and LSZ always inhibit the formation of Ca-P precipitates in SBF, and the inhibitory effect of BSA was more obvious that of LSZ. Protein presence can reduce the crystallinity of Ca-P precipitates. The crystal structure of Ca-P precipitates did not change when proteins were present, but the possibility of the formation HA, instead of another Ca-P phase increased both in vitro and in vivo. The analysis based on classical crystallization and growth theories indicated that proteins present in SBF reduced the driving force of nucleation and the nucleation rates by decreasing the effective level of supersaturation in SBF. The proteins can affect Ca-P nucleation by changing the interfacial energies in SBF. However, protein addition in SBF does not change the basic thermodynamic nature of HA and OCP formation. The growth rate of Ca-P in SBF can be significantly reduced through protein addition and the degree of growth reduction is highly dependent on the protein size. The protein effects on the interfacial energy were also investigated by the MD simulations. The results revealed that HSA and LSZ promoted HA nucleation on the (001) and (100) planes, HSA inhibited HA nucleation on the (110) plane. The MD simulations showed the characteristics of absorption of acidic Human serum albumin (HSA) and basic LSZ on the OCP and HA crystallographic planes. The results indicated that basic LSZ is more favorable for adsorption on OCP and HA than acidic HSA. HSA and LSZ adsorbed onto OCP (001) preferentially. HSA adsorbed onto HA (110) surface preferentially, but the selective adsorption of LSZ is not obvious. The MD simulations revealed characteristics of the interaction energy between proteins and HA surfaces, the binding/nucleation/adsorption sites of HA and proteins, and the structure of Ca-P clusters were analyzed. It was found that the basic residues of proteins played a more important role in the adsorption process than the acidic residues. Basic residues were more likely to adsorb on HA surfaces than bind to P ions in solution. HPO42- play more important role in the nucleation process than Ca2+ in solution. Single basic residue was more propitious to nucleate than single acidic residue, but the inducing nucleation by joint acidic/basic residues was the most favorable. HSA has greater ability to induce Ca-P nucleation than LSZ due to its better conformation and arrangement of acidic/basic residues (sequence). The amorphous Ca-P clusters formed preferentially whether in solution or on HA surfaces and proteins. The structure of OCP (100) and HA (001) were most favorable in the Ca-P clusters and HA structure is more favorable to form on proteins. In summary, this study advanced our understanding of Ca-P formation under the regulations of proteins by experimental, theoretical and computational approaches. It should shed light on insights into biomineralization processes.