Electrostatic origin of the mechanochemical rotary mechanism and the catalytic dwell of F1-ATPase

Abstract

Understanding the nature of energy transduction in life processes requires a quantitative description of the energetics of the conversion of ATP to ADP by ATPases. Previous attempts to do so have provided an interesting insight but could not account for the rotary mechanism by a nonphenomenological structure/energy description. In particular it has been very challenging to account for the observations of the 80°and 40°rotational substates, without any prior information about such states in the simulation procedure. Here we use a coarse-grained model of F1-ATPase and generate, without the adjustment of phenomenological parameters, a structure-based free energy landscape that reproduces the energetics of the mechanochemical process. It is found that the landscape along the relevant rotary path is determined by the electrostatic free energy and not by steric effects. Furthermore, the generated surface and the corresponding Langevin dynamics simulations identify a hidden conformational barrier that provides a new fundamental interpretation of the catalytic dwell and illuminate the nature of the energy conversion process.bioenergetics | chemical-conformational coupling | molecular motors | coarse grain model U nderstanding the energetics of the biological conversion of ATP to ADP is crucial for elucidating the nature of energy transduction in life processes and also for practical understanding of the action of molecular motors (1, 2). At present it seems that the detailed nature of this biological energy conversion process has remained a major puzzle (1-7). For example, despite the fact that the structures of several ATPases have been elucidated (e.g., refs. 4 and 8) and recent advances in detailed elucidation of some key steps have been made (9-11), it is not completely clear at what stage in the reaction energy is actually released and, in turn, what is the nature of the energy conversion process. Some workers have suggested that the major source of the energy release is the conversion of the free energy of ATP binding into elastic strain, which is subsequently released by a coordinated and tightly coupled conformational mechanism (6). It was also postulated that the energy conversion involves an inertial energy release (12), whereas our works (13, 14) have suggested that the energetics is associated with the electrostatic work, and the origin of the free energy change involves a significant contribution from the charge separation in solution outside the ATPase active sites. Furthermore, biochemical and structural studies have provided a molecular model for the action of ATPases (1-4), and remarkable phenomenological analyses (6, 7) indicated what are the conditions for effective action. However, we still do not have a clear structure function correlation that involves both the chemistry and the conformational coupling. The challenge became even more exciting in view of the remarkable progress in single-molecule studies that directly visualized the γ-subunit rotation in a unidirectional way, while revealing several...

Why nature really chose phosphate

“…The functional path is shown using a dashed white line. This figure was originally presented in (Mukherjee & Warshel, 2011). problem far beyond anything that has been obtained so far from other studies of the system, and can provide consistent insight into the events occurring in the F 1 -ATPase system. Now several works have proposed a steric mechanism (Koga & Takada, 2006 ;Pu & Karplus, 2008), or a somewhat related elastic spring model (Czub & Grubmueller, 2011), and asserted that such a mechanism emerged from their calculations.…”

“…38 is somewhat tentative and simplified, nevertheless, even this advances our understanding of the (Mukherjee & Warshel, 2011). This figure was originally presented in (Mukherjee & Warshel, 2011). Fig.…”

“…The stage between C and Ba may involve three nucleotides supporting a tri-site mechanism (not shown explicitly). This figure was originally presented in (Mukherjee & Warshel, 2011). the ATP state, relative to its energy in D, and probably as a result of a shift of the electrostatic potential from P b to halfway between P b and P c . Now, the large electrostatic repulsion between the ADP+P i fragments becomes relevant in the BpC process, where there exists an electrostatic cost toward assembling the fragments of the ADP+P i system.…”

“…Moreover, we examined the nature of the solvation effects in this process by a range of solvation models, and obtained a consensus result that not only is the bond breaking process making a significant contribution to the overall energetics, but also, this plays a significant part in the friction and dielectric compensation in this reaction, though more detailed careful entropic studies may be needed to explore this issue further. Turning our attention back to the reaction in ATPases, we would like to point out to the reader that a consensus summary of the energetics of the different steps in the process in F1-ATPase is given in Table S1 of Mukherjee & Warshel, 2011. Obviously, this is still a work in progress ; however, it also illustrates the need for careful experimental and theoretical analyses of this problem.…”

“…In order to address this issue, we recently (Mukherjee & Warshel, 2011) used our CG model (Messer et al 2010) to simulate the F 1 -ATPase parts, consisting of three a/b-dimers and the c-subunit. The CG model was first used to evaluate the overall electrostatic free-energy surface, without incorporating the effect of the ligands and/or chemistry, and the corresponding results are described in Fig.…”