The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.