Aptamers are DNA, RNA, and peptides that have a specific affinity for particular substances [1, 2], such as small molecules[3, 4], ions[5, 6], proteins [7, 8], cells [9, 10], and organisms [11, 12]. Although antibodies have similar properties to aptamers, aptamers have many advantages. For example, aptamers are less immunogenic, have better specificity, have higher affinity to their targets, and exhibit less non-specific cross-reactivity than antibodies [13–15]. Because aptamers are selected in vitro, they can be used against a broad range of targets, such as toxic and non-immunogenic substances. Compared with antibodies, aptamers are stable to heat  and pH , and resistant to organic solvents. Thus, one can select target molecules under non-physiological conditions. Moreover, unlike antibodies, aptamers can undergo several denaturation/refolding cycles without loss of activity. One can mass-produce aptamers by chemical synthesis at low production costs. Accordingly, researchers use aptamers in a broad range of fields, such as diagnostics and therapy[1, 21–25], drug delivery[26–28], and biosensors[29–32].
Sensitive detection of metals based on the affinity and specificity of aptamers is an active field of research in environmental monitoring and medical diagnosis. In medicine, the concentrations of various metals in vivo can be used as biomarkers, measurable indicators of biological conditions. For example, titanium and its alloys see use in the production of many medical implants, such as artificial bones and joints. Recent studies suggest that titanium-based implants exhibit wear and corrosion in physiological environments, releasing titanium particles into the surrounding tissues and blood. Because titanium is highly insoluble and can lead to tissue injury, researchers need accurate and facile measurements of the titanium concentration in blood. However, precise measurements require technical equipment, which makes routine monitoring difficult . Using aptamers in blood tests would enable the concentration of various metals in blood, such as titanium, to be measured at a low cost. This would solve the problems associated with conventional testing methods. Thus, it is necessary to develop aptamers with specific and high affinity for various metals.
Numerous peptide aptamers with a specific affinity for various inorganic surfaces has been developed [34–40]. Sano et al. identified a peptide TBP-1 (RKLPDAPGMHTW) that specifically binds to Ti by using phage display and suggested that RKLPDA (minTBP-1) in the peptide sequence is pertinent to binding to the Ti surface. Initial studies on the binding affinity suggest that minTBP-1 has affinities for Ti, Si, and Ag; but not for Au, Cr, Pt, Sn, Zn, Cu, and Fe. Regarding the roles of amino acid residues in the minTBP-1 sequence, alanine substitution experiments suggest that mutation of a neutral proline in the sequence decreases these affinities; in contrast, mutation of a charged lysine in the sequence increases them. Skelton et al. obtained similar results using molecular dynamics simulations. They suggested that changes in the flexibility of minTBP-1 (due to mutations of proline) and changes in the stability of the molecular structure in the adsorbed state (due to mutations of lysine) are pertinent factors. Furthermore, the interactions of the charged residues in the sequence—Arg, Asp, and Lys—with the water layers structured on the TiO2 surface drive the initial stage of adsorption of minTBP-1. These results suggest the importance of interfacial water layers in interactions between peptides and TiO2 surfaces.
Schneider et al. performed molecular dynamics simulations to analyze the adsorption of minTBP-1 on TiO2 and SiO2 surfaces. Sultan et al. suggested that peptide structures and sequences are pertinent to binding affinity, and evaluated various titanium-binding peptides Ti-1 (QPYLFATDSLIK) and Ti-2 (GHTHYHAVRTQT) from the standpoint of entropy and enthalpy. These two peptide sequences differ substantially in terms of the overall balance between hydrophobic and charged residues. Hydropathy scores indicate that Ti-1 has stronger hydrophobicity. However, quartz crystal microbalance experiments show that these two peptides have similar binding affinities for the TiO2 surface. Molecular dynamics simulations suggest that Ti-1 is an entropically driven binder, with no strong anchor residues, whereas Ti-2 is an enthalpically guided binder, featuring a high number of periodically spaced anchor residues along the chain length.
Although many studies have been published on the interactions between biomolecules and inorganic surfaces, researchers still do not fully understand why particular peptides have specific binding affinities for inorganic surfaces. By elucidating the fundamentals of specific recognition between peptides and inorganic surfaces, novel peptide aptamers can be rationally designed on the basis of the properties of the target inorganic surfaces, which will reduce research and development costs. Therefore, it is necessary to understand how the properties of peptides, which are determined by their steric structures and amino acid sequences, affect their interactions with inorganic surfaces and how one can tailor these properties to modulate affinity.
We focused on hydrophobic groups in amino acids to understand their affinity for solid walls. We used virtual amino acid molecules based on arginine. In physiological environments, metal surfaces are oxidized and positively or negatively charged . Assuming a negatively charged metal solid surface, we simulated virtual solid walls with downward dipole moments on the surface. We performed molecular dynamics simulations to evaluate changes in the adsorption states of amino acids and changes in the magnitude of the dipole moments by calculating the free energy.