Kinetic Modeling of ATP Synthesis by ATP Synthase and Its Mechanistic Implications

Nath, Sunil; Jain, Siddhartha

doi:10.1006/bbrc.2000.2774

Cited by 29 publications

(66 citation statements)

References 20 publications

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“…Moreover, the molecular basis of cooperativity in ATP synthase remains unelucidated, despite almost three decades of experimental effort! Finally, our kinetic analysis necessitates that in the steady state physiological mode of ATP synthesis, product ATP release must precede substrate ADP binding [19], in agreement with the latest experimental evidence by direct optical probes [38], while, according to all versions of the binding change mechanism from 1973 to 2000, ADP binding must precede ATP release or be simultaneous with it. In the latest modification [37], the L site has no real role to play.…”

Section: Further Specific Difficulties Associated With the Binding Chsupporting

confidence: 65%

“…Moreover, in this mode, in Boyer's bi-site mechanism, MgATP binds to the low affinity O site, but the medium affinity L site is left unfilled, which is a problem, as discussed [43]. Further, negative binding cooperativity and positive catalytic cooperativity need not occur simultaneously, as discussed by us [19], and as shown by recent experimental evidence [44].We have also shown from first principles that there is absence of site-site cooperativity in ATP synthase under physiological steady state operating conditions [19]; in fact, there is no need for cooperativity [18]. Moreover, the molecular basis of cooperativity in ATP synthase remains unelucidated, despite almost three decades of experimental effort!…”

Section: Further Specific Difficulties Associated With the Binding Chmentioning

confidence: 94%

“…1). The molecular masses of the a, b, g, d, and e subunits in E. coli measure about 55,50,31,19, and 15 kDa, while the a, b, and c subunits have molecular masses of 30, 17, and 8 kDa, respectively [21][22][23][24][25][26][27][28][29][30]. The F 0 and F 1 domains are linked by two slender stalks [21][22][23][24][25][26][27][28][29][30].…”

Section: Subunit Compositionmentioning

confidence: 99%

“…It appeared that a completely fresh and original hypothesis was needed that could explain the wealth of existing data and better withstand further experimental challenge. In a series of papers during 1998-2001, Nath and co-workers proposed the torsional mechanism of energy transduction and ATP synthesis [16][17][18][19][20]56].…”

Section: Introduction and Brief Historymentioning

confidence: 99%

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The Molecular Mechanism of ATP Synthesis by F1F0-ATP Synthase: A Scrutiny of the Major Possibilities

Nath

2002

Tools and Applications of Biochemical Engineering Science

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165

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There is a complicated hypothesis which usually entails an element of mystery and several unnecessary assumptions. This is opposed by a more simple explanation which contains no unnecessary assumptions. The complicated one is always the popular one at first, but the simpler one, as a rule, eventually is found to be correct. This process frequently requires 10 to 20 years. The reason for this long time lag was explained by Max Planck. He remarked that "Scientists never change their minds, but eventually die." J.H. NorthropA critical goal of metabolism in living cells is the synthesis of adenosine triphosphate (ATP). ATP is synthesized by the enzyme F 1 F 0 -ATP synthase. This enzyme, the smallest-known molecular machine, couples proton translocation through its membrane-embedded, hydrophobic domain, F 0 , to the synthesis of ATP from adenosine diphosphate (ADP) and inorganic phosphate (P i ) in its soluble, hydrophilic headpiece, F 1 . Animals, plants and microorganisms all capture and utilize energy by this important chemical reaction. How does it occur?The binding change mechanism and the torsional mechanism of energy transduction and ATP synthesis are two mechanisms that have been proposed in the literature. According to the binding change mechanism (which considers reversible catalysis and site-site cooperativity), energy is required primarily for release of synthesized ATP, but not for its synthesis. On the other hand, according to the torsional mechanism (which considers an irreversible mode of catalysis and absence of cooperativity), all the elementary steps require energy, and the ionprotein interaction energy obtained from the ion gradients is used to synthesize ATP, for P i binding, and for straining the b-e bond in order to enable ADP to bind. The energy to release preformed ATP from the tight catalytic site (b DP ) is provided by the formation of the b-e ester linkage. First, the central features of these mechanisms are clearly delineated. Then, a critical scrutiny of these mechanisms is undertaken. The predictions of the torsional mechanism are listed. In particular, how the torsional mechanism deals with the specific difficulties associated with other mechanisms, and how it seeks to explain a wealth of structural, spectroscopic, and biochemical data is discussed in detail. Recent experimental data in support of the mechanism are presented. Finally, in view of the molecular machine nature of energy transduction, the indispensability of applying engineering tools at the molecular level is highlighted. This paves the way for the development of a new field: Molecular Physiological Engineering.

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Section: Further Specific Difficulties Associated With the Binding Chsupporting

confidence: 65%

Section: Further Specific Difficulties Associated With the Binding Chmentioning

confidence: 94%

Section: Subunit Compositionmentioning

confidence: 99%

Section: Introduction and Brief Historymentioning

confidence: 99%

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The Molecular Mechanism of ATP Synthesis by F1F0-ATP Synthase: A Scrutiny of the Major Possibilities

Nath

2002

Tools and Applications of Biochemical Engineering Science

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165

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“…Usually, the cycle is described by four occupancy states: Empty (E) 7 ADP (D) 7 ADP⅐P i (DP) 7 ATP (T) (see also Supporting Text). On this time scale, the transitions between these states can be regarded as instantaneous; thus, the steps in the kinetic cycle can be treated as Markov transitions between discrete reaction coordinates (29,30). However, for motor proteins, the power stroke is a mechanical motion that is directly affected by external mechanical forces: the torque from F o , in this case.…”

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confidence: 99%

Making ATP

Xing

Liao

Oster

2005

Proc. Natl. Acad. Sci. U.S.A.

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We present a mesoscopic model for ATP synthesis by F1Fo ATPase. The model combines the existing experimental knowledge of the F1 enzyme into a consistent mathematical model that illuminates how the stages in synthesis are related to the protein structure. For example, the model illuminates how specific interactions between the ␥, , and ␣3␤3 subunits couple the Fo motor to events at the catalytic sites. The model also elucidates the origin of ADP inhibition of F1 in its hydrolysis mode. The methodology we develop for constructing the structure-based model should prove useful in modeling other protein motors.ATP synthase ͉ ATP synthesis ͉ F1Fo ATPase M echanochemical proteins convert the energy of chemical bonds into mechanical forces and, in the case of one ancient protein, vice versa. ATP synthase (also called F 1 F o ATPase) uses the energy stored in a transmembrane electrochemical gradient to synthesize ATP. ATP synthase is unique in combining two rotary molecular motors in one protein so that the assembly can either synthesize ATP or pump ions across a membrane, depending on which motor dominates. The F 1 F o system has been studied extensively both experimentally and theoretically, so the basic operating principles of both the F o and F 1 motors are understood at near molecular detail (e.g. refs. 1-5).Modeling of mechanoenzymes takes three general approaches. Molecular dynamics (MD) attempts to account for the motion of every atom, and sometimes the surrounding water and other chemical species. Kinetic models represent the transitions between small numbers of chemical (Markov) states. Markov-FokkerPlanck (MFP) models lie somewhere between the atomic detail of MD and the phenomenology of kinetic models (6). These models describe the geometric motion along a few ''collective coordinates'' that describe the protein's major conformational movements. Motion is driven by forces derived from a set of potential functions assigned to each coordinate, with Markov jumps between the potentials corresponding to chemical transitions. MFP models generalize kinetic models by replacing the discrete kinetic states with potential functions representing collective spatial coordinates. The distinctions between, and relative advantages of, each of these models have been discussed in detail elsewhere (6). A prominent feature of MFP models is that structural and dynamical information can be included in the models without the computational load of MD models. In this work, we take this approach. We emphasize that MFP models complement MD and kinetic models; each has its proper place in understanding a mechanochemical system as complex as a protein motor.In constructing an MFP model, the central step is to identify the important degrees of freedom that must be treated explicitly, and construct a set of free energy potential surfaces with these degrees of freedom as geometrical coordinates. Identification of the collective coordinates can often be inferred from the protein structure and its biochemistry (7). Normal mode analysis also c...

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Molecular Mechanisms of Energy Transduction in Cells: Engineering Applications and Biological Implications

Nath

2003

Biotechnology in India II

123

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Kinetic Modeling of ATP Synthesis by ATP Synthase and Its Mechanistic Implications

Cited by 29 publications

References 20 publications

The Molecular Mechanism of ATP Synthesis by F1F0-ATP Synthase: A Scrutiny of the Major Possibilities

The Molecular Mechanism of ATP Synthesis by F1F0-ATP Synthase: A Scrutiny of the Major Possibilities

Making ATP

Molecular Mechanisms of Energy Transduction in Cells: Engineering Applications and Biological Implications

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