my %acgt; @acgt{ qw[ a c g t ] } = 0 .. 3;

sub encode {
    my $string = lc shift;
    die "String '$string' >16 chars" if length $string > 16;
    my $bits = '';
    vec( $string, $_, 2 ) = $acgt{ substr $string . 'a' x 16, $_, 1 }
        for 0 .. 15;
    return unpack 'N',  $bits;
}

##</code><code>##

my $lookup = '';
while( <SMALLFILE> ) {
    chomp;
    vec( $lookup, encode( $_), 1 ) = 1;
}

##</code><code>##

while( <BIGFILE> ) {
    chomp;
    print if vec( $lookup, encode( $_ ), 1 );
}