Abstract
The catalytic role of near attack conformations (NACs), molecular states that lie on the pathway between the ground state (GS) and transition state (TS) of a chemical reaction, is not understood completely. Using a computational approach that combines Bürgi–Dunitz theory with all-atom molecular dynamics simulations, the role of NACs in catalyzing the first stages of HIV-1 protease peptide hydrolysis was previously investigated using a substrate that represents the recognized SP1-NC cleavage site of the HIV-1 Gag polyprotein. NACs were found to confer no catalytic effect over the uncatalyzed reaction there ( Δ Δ G N ‡ ∼ 0 kcal/mol). Here, using the same approach, the role of NACs across multiple substrates that each represent a further recognized cleavage site is investigated. Overall rate enhancement varies by | Δ Δ G ‡ | ∼ 12–15 kcal/mol across this set, and although NACs contribute a small and approximately constant barrier to the uncatalyzed reaction (< Δ G N ‡ u > = 4.3 ± 0.3 kcal/mol), they are found to contribute little significant catalytic effect ( | Δ Δ G N ‡ | ∼ 0–2 kcal/mol). Furthermore, no correlation is exhibited between NAC contributions and the overall energy barrier ( R 2 = 0.01). However, these small differences in catalyzed NAC contributions enable rates to match those required for the kinetic order of processing. Therefore, NACs may offer an alternative and subtle mode compared to non-NAC contributions for fine-tuning reaction rates during complex evolutionary sequence selection processes—in this case across cleavable polyproteins whose constituents exhibit multiple functions during the virus life-cycle.
Highlights
According to Pauling [1], rate enhancement due to enzyme catalysis stems from the tighter binding of the transition state (TS) as compared to the ground state (GS) of a substrate undergoing chemical reaction
The molecular origin of rate increase can stem from a number of processes such as quantum mechanical tunneling [4,5,6], non-equilibrium dynamics [7,8,9,10,11,12], changes in substrate flexibility between the TS and the GS [13,14,15], preorganization of electrostatic interactions that favor formation of the TS [16,17,18,19,20,21,22] and the thermodynamic stabilization of near attack conformations (NACs)—GS conformations that lie on the transition path closer to the TS [13,23,24,25,26,27,28,29,30]
Computational studies have previously revealed the existence of a small but significant thermodynamic barrier contributed by the formation of near attack conformations (NACs) that lie on the transition path of the peptide hydrolysis reaction catalyzed by HIV-1 protease [31]
Summary
According to Pauling [1], rate enhancement due to enzyme catalysis stems from the tighter binding of the transition state (TS) as compared to the ground state (GS) of a substrate undergoing chemical reaction. This is thermodynamically equivalent to a negative activation free energy difference (∆∆G‡ ) between the catalyzed (∆G‡c ) and the uncatalyzed (∆G‡u ) reaction where:. The molecular origin of rate increase can stem from a number of processes such as quantum mechanical tunneling [4,5,6], non-equilibrium dynamics [7,8,9,10,11,12], changes in substrate flexibility between the TS and the GS [13,14,15], preorganization of electrostatic interactions that favor formation of the TS [16,17,18,19,20,21,22] and the thermodynamic stabilization of near attack conformations (NACs)—GS conformations that lie on the transition path closer to the TS [13,23,24,25,26,27,28,29,30].
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