The corona-like spikes or peplomers on the surface of the virion under electronicmicroscope are the most striking features of coronaviruses. The S (spike) proteinis the largest structural protein, with 1,255 amino acids, in the viral genome. Itsstructure can be divided into three regions: a long N-terminal region in the exte-rior, a characteristic transmembrane (TM) region, and a short C-terminus in theinterior of a virion. We detected fifteen substitutions of nucleotides by comparisonswith the seventeen published SARS-CoV genome sequences, eight (53.3%) of whichare non-synonymous mutations leading to amino acid alternations with predictedphysiochemical changes. The possible antigenic determinants of the S protein arepredicted, and the result is confirmed by ELISA (enzyme-linked immunosorbentassay) with synthesized peptides. Another profound finding is that three disulfidebonds are defined at the C-terminus with the N-terminus of the E (envelope) pro-tein, based on the typical sequence and positions, thus establishing the structuralconnection with these two important structural proteins, if confirmed. Phyloge-netic analysis reveals several conserved regions that might be potent drug targets.