Oral commensal Streptococcus gordonii proteolytically cleave the salivary PRP-1 polypeptide into an RGRPQ innate peptide. The Arg and Gln termini are crucial for RGRPQ-mediated ammonia production and proliferation by S. gordonii SK12 and adhesion inhibition and desorption by Actinomyces naeslundii T14V, respectively. Here we have applied (i) a multivariate approach using RGRPQ-related peptides varied at amino acids 2, 3, and 4 simultaneously and (ii) size and N-and C-terminal modifications of RGRPQ to generate structure activity information. While the N-terminal arginine motif mediated ammonia production independent of peptide size, other responses required more or less full-length peptide motifs. The motifs for adhesion inhibition and desorption were the same. The adhesion and proliferation motifs required similarily a hydrophobic/low polarity amino acid 4 but differentially a hydrophilic or hydrophobic character of amino acids 2/3, respectively; polar peptides with small/hydrophilic and hydrophilic amino acids 2 and 3, respectively, had high adhesion inhibition/desorption activity, and lipophilic peptides with large/hydrophobic amino acids 2 and 3 had high proliferation activity. Accordingly, while RIWWQ had increased proliferation but abolished adhesion/desorption activity, peptides designed with hydrophilic amino acids 2 and 3 were predicted to behave in the opposite way. Moreover, a RGRPQ mimetic for all three responses should mimic small hydrophilic, large nitrogen-containing, and hydrophobic/low polarity amino acids 2, 3, and 4, respectively. Peptides fulfilling these criteria were 1-1.6-fold improved in all three responses. Thus, both mimetics and peptides with differential proliferation and adhesion activities may be generated for evaluation in biofilm models.Saliva confers infection resistance and wound healing to oral tissue surfaces (1, 2). The saliva innate defense resides in general properties, such as clearance and pH, and specific innate (poly)peptide functions. These innate peptide functions control adhesion and colonization of commensal and pathogenic microorganisms as well as tissue homeostasis (1, 3, 4).Acidic, basic, and glycosylated proline-rich proteins (PRPs), 2 encoded by six genes on chromosome 12p13.2 (5), are abundant and polymorphic proteins in saliva (1, 6). Acidic PRPs mediate adhesion of commensal Streptococcus and Actinomyces species (7, 8), neutralize dietary tannins (polyphenols), and interact with calcium (1). These interactions occur through the C-terminal, proline-rich middle and phosporylated N-terminal domains, respectively (1). PRPs are subject to endogenous and bacterial proteolysis, generating a wide range of peptide derivatives in saliva (6, 9, 10). Both allelic PRP variants and small size peptides derived thereof coincide with susceptibility or resistance to caries (11,12). The allelic acidic PRP variant Db coincides with caries susceptibility and adhesion of Streptococcus mutans (12), implicated in caries. The other acidic PRP variants (e.g. PRP-1 and PRP-2) coincide...