Both the crystal structures of the HIV-1 gp120 core bound by the CD4 and antigen 17b, and the SIV gp120 core pre-bound by CD4 are known. We built the homology models of gp120 with loops V3 and V4 in the CD4-complex, CD4-free and CD4-unliganded states, and models of the 375 S/W and 423 I/P mutants in the CD4-free and unliganded states, respectively. CONCOORD was utilized for generating ensembles of the seven gp120 models that were analyzed by essential dynamics analyses to identify their preferred concerted motions. The revealed large-scale concerted motions are related to either the receptor association/release or the conformational transition between different conformational states. Essential subspace overlap analyses were performed to quantitatively distinguish the preference for conformational transitions between states of the gp120 mutants and further to ascertain what kind of conformational state that the mutants prefer to adopt. Results indicate that the 375 S/W mutant, in which the tryptophan indole group is predicted to occupy the phe43 pocket in the gp120 interior, favors a conformation close to the CD4-bound state. However, the other mutant 423 I/P inclines to prevent the formation of bridging sheet and stabilize the conformation in the unliganded state. Our theoretical analyses are in agreement with experimentally determined mutation effects, and can be extended to a new approach to design or screen mutants that have effects on conformation/function of a protein.