Pseudopeptides based on poly(l-lysine isophthalamide) backbone have emerged as promising drug delivery candidates due to their pH-activated membrane disruption ability. To gain molecular understanding on these novel polymeric species, we have constructed force-field parameters and simulated the behaviors of polymers with and without phenylalanine grafted as side chains under conditions compatible with different pHs. The free energy changes upon polymer permeation through membrane were calculated using the umbrella sampling technique. We show that both polymers with and without grafts interact better with the membrane under conditions compatible with lower pH. The conformational states of the polymers were investigated in water and at a water-membrane interface. On the basis of Markov state modeling results, we propose a possible advantage of the grafted polymer over the ungrafted polymer for membrane rupture because of its quicker conformational rearrangement kinetics.