Abstract: Understanding how corals adapt to changes in seawater carbonate chemistry is crucial for developing effective coral conservation strategies. Research to date has mostly focused on short-term experiments, overlooking long-term evolutionary effects. Here, we investigated the link between short-term stress responses and long-term genetic adaptations in the coral species Porites pukoensis through experiments under varying CO₂ and alkalinity conditions. Our results showed that alkalinity enrichment significantly increased coral calcification rates by 35%-45% compared to high CO₂ treatment, highlighting the potential of alkalinity enrichment to mitigate acidification impacts. Corals modulated relative expression levels of basic and acidic proteins in response to changes in seawater carbonate chemistry in the stress experiments. Genomic data revealed that this mechanism has been evolutionarily fixed in various organisms adapting to seawater carbonate chemistry. Additionally, both experimental and genomic results showed that extracellular matrix proteins, like collagen with von Willebrand factor type A domain, were modified in response to distinct carbonate environments. Molecular dynamics simulations and in-vitro experiments demonstrated that the structural stability of these proteins contributes to coral resilience under acidified conditions. This study established an integrated framework combining stress experiments, multi-omics analyses, molecular simulations, and in-vitro validation to identify key proteins involved in coral adaptation to acidification.