We investigate the effect of side chain on the first-order hyperpolarizability in a-helical polyalanine peptide with the 10th alanine mutation (Acetyl(ala)(9)X(ala)(7)NH2). Structures of various substituted peptides are optimized by ONIOM (DFT: AM1) scheme, and then linear and nonlinear optical properties are calculated by SOS//CIS/6-31G* method. The polarizability and first-order hyperpolarizability increase obviously only when 'X' represents phenylalanine, tyrosine and tryptophan. We also discuss the origin of nonlinear optical response and determine what caused the increase of first-order hyperpolarizability. Our results strongly suggest that side chains containing benzene, phenol and indole have important contributions to first-order hyperpolarizability. (C) 2012 Elsevier B. V. All rights reserved.