Investigating the flap dynamics of HIV-1 protease using multiple force fields

Date of Award


Document Type


Degree Name

Bachelor of Science



First Advisor

Dr. Carol A. Parish


The World Health Organization estimates that there are 34 million people living with HIV. In 2010, 2.7 million more people were newly infected. HIV protease is an essential enzyme for the maturation of the HIV virus that cleaves three previral polyproteins. The HIV virus mutates at a rapid pace, resulting in the emergence of HIV resistance to new protease inhibitors. This study attempts to correlate experimental evidence with long time-scale visual computer simulations using the flap tips to present a better definition of the range of flap opening. Wu et al., in 2003 provided evidence that the flap tips of HIV-1 protease control enzyme activity. Although HIV-1 protease flap dynamics has been studied intensely, a force field comparison has never been conducted. By contrasting the results of Charmm and Amber force fields through long time-scale simulations, we can ensure that the computational results are force field independent and not an artifact of the simulations. This data will confirm the existence of four protease conformational states: closed, semi-open, open, and wide-open states and this can be used for more subsequent study of new HIV-1 protease inhibitors. Simulations were conducted using two force fields (Amber ff99SB and Charmm27) with two starting structures “closed” (1HVR.pdb) and “semi-open” (1HHP.pdb). All four conformations were sampled using both force fields. The relative conformational distribution observed experimentally was best supported by the Charmm27 force field. Additionally, the use of an ILE50 metric for measuring conformational populations over the previously used LYS55 metric for conformational states is proposed.


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