scholarly journals Intrinsic Free Energy of the Conformational Transition of the KcsA Signature Peptide from Conducting to Nonconducting State

2008 ◽  
Vol 4 (9) ◽  
pp. 1541-1554 ◽  
Author(s):  
Ilja V. Khavrutskii ◽  
Mikolai Fajer ◽  
J. Andrew McCammon
Keyword(s):  
Free Energy ◽  
Conformational Transition ◽  
Signature Peptide

scholarly journals Free energy landscape for the entire transport cycle of triose-phosphate/phosphate translocator

2017 ◽  
Author(s):  
Mizuki Takemoto ◽  
Yongchan Lee ◽  
Ryuichiro Ishitani ◽  
Osamu Nureki
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Conformational Transition ◽  
Substrate Binding ◽  
Energy Landscape ◽  
Umbrella Sampling ◽  
Free Energy Landscape ◽  
Coupling Mechanism ◽  
Triose Phosphate ◽  
Phosphate Translocator

AbstractSecondary active transporters translocate their substrates using the electrochemical potentials of other chemicals, undergoing large-scale conformational changes. Despite extensive structural studies, the atomic details of the transport mechanism still remain elusive. Here we performed a series of all-atom molecular dynamics simulations of the triose-phosphate/phosphate translocator (TPT), which exports organic phosphates in the chloroplast stroma in strict counter exchange with inorganic phosphate (Pi). Biased sampling methods, including string method and umbrella sampling, successfully reproduced the conformational changes between the inward– and outward-facing states, along with the substrate binding. The free energy landscape of this entire TPT transition pathway demonstrated the alternating access and substrate translocation mechanisms, which revealed Pi is relayed by positively charged residues along the transition pathway. Furthermore, the conserved Glu207 functions as a “molecular switch”, linking the local substrate binding and the global conformational transition. Our results provide atomic-detailed insights into the energy coupling mechanism of antiporter.

scholarly journals Application of rate-equilibrium free energy relationship analysis to nonequilibrium ion channel gating mechanisms

2009 ◽  
Vol 134 (2) ◽  
pp. 129-136 ◽  
Author(s):  
László Csanády
Keyword(s):  
Free Energy ◽  
Ion Channels ◽  
Transition State ◽  
Ion Channel ◽  
Conformational Transition ◽  
Limited Information ◽  
Relationship Analysis ◽  
Gating Mechanisms ◽  
Gating Mechanism ◽  
Transition State Structures

Rate-equilibrium free energy relationship (REFER) analysis provides information on transition-state structures and has been applied to reveal the temporal sequence in which the different regions of an ion channel protein move during a closed–open conformational transition. To date, the theory used to interpret REFER relationships has been developed only for equilibrium mechanisms. Gating of most ion channels is an equilibrium process, but recently several ion channels have been identified to have retained nonequilibrium traits in their gating cycles, inherited from transporter-like ancestors. So far it has not been examined to what extent REFER analysis is applicable to such systems. By deriving the REFER relationships for a simple nonequilibrium mechanism, this paper addresses whether an equilibrium mechanism can be distinguished from a nonequilibrium one by the characteristics of their REFER plots, and whether information on the transition-state structures can be obtained from REFER plots for gating mechanisms that are known to be nonequilibrium cycles. The results show that REFER plots do not carry information on the equilibrium nature of the underlying gating mechanism. Both equilibrium and nonequilibrium mechanisms can result in linear or nonlinear REFER plots, and complementarity of REFER slopes for opening and closing transitions is a trivial feature true for any mechanism. Additionally, REFER analysis provides limited information about the transition-state structures for gating schemes that are known to be nonequilibrium cycles.

scholarly journals Conformational Change of H64 and Substrate Transportation: Insight Into a Full Picture of Enzymatic Hydration of CO2 by Carbonic Anhydrase

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuzhuang Fu ◽  
Fangfang Fan ◽  
Yuwei Zhang ◽  
Binju Wang ◽  
Zexing Cao
Keyword(s):  
Free Energy ◽  
Carbonic Anhydrase ◽  
Proton Transfer ◽  
Energy Barrier ◽  
Conformational Transition ◽  
Md Simulations ◽  
Nucleophilic Attack ◽  
Free Energy Barrier ◽  
Full Picture ◽  
Key Residues

The enzymatic hydration of CO2 into HCO3− by carbonic anhydrase (CA) is highly efficient and environment-friendly measure for CO2 sequestration. Here extensive MM MD and QM/MM MD simulations were used to explore the whole enzymatic process, and a full picture of the enzymatic hydration of CO2 by CA was achieved. Prior to CO2 hydration, the proton transfer from the water molecule (WT1) to H64 is the rate-limiting step with the free energy barrier of 10.4 kcal/mol, which leads to the ready state with the Zn-bound OH−. The nucleophilic attack of OH− on CO2 produces HCO3− with the free energy barrier of 4.4 kcal/mol and the free energy release of about 8.0 kcal/mol. Q92 as the key residue manipulates both CO2 transportation to the active site and release of HCO3−. The unprotonated H64 in CA prefers in an inward orientation, while the outward conformation is favorable energetically for its protonated counterpart. The conformational transition of H64 between inward and outward correlates with its protonation state, which is mediated by the proton transfer and the product release. The whole enzymatic cycle has the free energy span of 10.4 kcal/mol for the initial proton transfer step and the free energy change of −6.5 kcal/mol. The mechanistic details provide a comprehensive understanding of the entire reversible conversion of CO2 into bicarbonate and roles of key residues in chemical and nonchemical steps for the enzymatic hydration of CO2.

scholarly journals Efficient fidelity control by stepwise nucleotide selection in polymerase elongation Abstract: Polymerases select nucleotides

2014 ◽  
Vol 2 (1) ◽  
pp. 141-160 ◽  
Author(s):  
Jin Yu
Keyword(s):  
Free Energy ◽  
High Speed ◽  
Heat Dissipation ◽  
Conformational Transition ◽  
Reaction Path ◽  
Error Reduction ◽  
Gene Replication ◽  
Elongation Cycle ◽  
The Right ◽  
Efficient Selection

Abstract Polymerases select nucleotides according to a template before incorporating them for chemical synthesis during gene replication or transcription. Efficient selection to achieve sufficiently high fidelity and speed is essential for polymerase function. Due to multiple kinetic steps detected in a polymerase elongation cycle, there exist multiple selection checkpoints to allow different strategies of fidelity control. In our current work, we examined step-by-step selections in an elongation cycle that have conformational transition rates tuned one at a time, with a controlled differentiation free energy between the right and wrong nucleotides at each checkpoint. The elongation is sustained at non-equilibrium steady state with constant free energy input and heat dissipation. It is found that a selection checkpoint in the later stage of a reaction path has less capability for error reduction. Hence, early selection is essential to achieve an efficient fidelity control. In particular, for an intermediate state, the selection through the forward transition inhibition has the same capacity for error reduction as the selection through the backward rejection. As with respect to the elongation speed, an initial screening is indispensible for maintaining high speed, as the wrong nucleotides can be removed quickly and replaced by the right ones at the entry. Overall, the elongation error rate can be repeatedly reduced through multiple selection checkpoints. This study provides a theoretical framework to guide more detailed structural dynamics studies, and to support rational redesign of related enzymes and devices.

scholarly journals An Empirical Energy Landscape Reveals Mechanism of Proteasome in Polypeptide Translocation

2021 ◽  
Author(s):  
Rui Fang ◽  
Jason Hon ◽  
Mengying Zhou ◽  
Ying Lu
Keyword(s):  
Free Energy ◽  
Atp Hydrolysis ◽  
Conformational Transition ◽  
Energy Landscape ◽  
Kinetic Properties ◽  
Cellular Functions ◽  
Kinetic Measurements ◽  
Novel Approach ◽  
Model Predictions ◽  
Atpase Subunits

The ring-like ATPase complexes in the AAA+ family perform diverse cellular functions that require coordination between the conformational transitions of their individual ATPase subunits. How the energy from ATP hydrolysis is captured to perform mechanical work by these coordinated movements is not known. In this study, we developed a novel approach for delineating the nucleotide-dependent free-energy landscape (FEL) of the proteasome's heterohexameric ATPase complex based on complementary structural and kinetic measurements. We used the FEL to simulate the dynamics of the proteasome and quantitatively evaluated the predicted structural and kinetic properties. The FEL model predictions were widely consistent with experimental observations in this and previous studies and suggested novel features of the mechanism of proteasomal ATPase. We find that the cooperative movements of the ATPase subunits result from the design of the ATPase hexamer entailing a unique free-energy minimum for each nucleotide-binding state. ATP hydrolysis dictates the direction of substrate translocation by triggering an energy-dissipating conformational transition of the ATPase complex.

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