Abstract
Proteins fold on a time scale incompatible with a mechanism of random search in conformational space thus indicating that somehow they are guided to the native state through a funneled energetic landscape. At the same time the heterogeneous kinetics suggests the existence of several different folding routes. Here we propose a scenario for the folding mechanism of the monomer of HIV–1 protease in which multiple pathways and milestone events coexist. A variety of computational approaches supports this picture. These include very long all-atom molecular dynamics simulations in explicit solvent, an analysis of the network of clusters found in multiple high-temperature unfolding simulations and a complete characterization of free-energy surfaces carried out using a structure-based potential at atomistic resolution and a combination of metadynamics and parallel tempering. Our results confirm that the monomer in solution is stable toward unfolding and show that at least two unfolding pathways exist. In our scenario, the formation of a hydrophobic core is a milestone in the folding process which must occur along all the routes that lead this protein towards its native state. Furthermore, the ensemble of folding pathways proposed here substantiates a rational drug design strategy based on inhibiting the folding of HIV–1 protease.
Highlights
The protease of Human Immunodeficiency Virus type 1 (HIV– 1–PR) is a dimer in its catalytic competent form (Fig. 1)
We label different set of interactions, namely b1–b3 stands for the interaction between b1 and b3, while folding nucleus (FN) refers to the interaction between fragments 24–34 and 83–92
The simulations of the HIV–1–PR monomer performed with theoretical models of different complexity suggested that the hightemperature unfolding and the folding mechanism of this protein are heterogenous processes
Summary
The protease of Human Immunodeficiency Virus type 1 (HIV– 1–PR) is a dimer in its catalytic competent form (Fig. 1). Studying the folding of the HIV–1–PR monomer is the first step in the comprehension of the whole enzyme formation. HIV–1–PR is one of the main targets of Acquired ImmunoDeficiency Syndrome therapies as it performs an essential function in the HIV life cycle by cleaving the viral poly-protein and producing the components that are needed for the mature virus assembly. An alternative strategy for neutralizing the HIV–1–PR function consists in inhibiting the formation of the protease by interfering either with the folding process of the monomer or with its dimerization [7,8]. It has been suggested that the dimer is stabilized by the substrate. In such a scenario it would be more advantageous to target the monomer folding
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
