Wide Transition-State Ensemble as Key Component for Enzyme Catalysis

This repository contains data and findings from the study titled "Wide Transition-State Ensemble as Key Component for Enzyme Catalysis". It includes the following compressed files:

1. MSMD_simulations: Contains the MSMD simulation data, including topology, work vs. reaction coordinate, trajectories, and inputs. Both forward and backward reactions are included. Data for all systems are located in this folder: ADP/ADP with Mg²⁺, ADP/ADPH without Mg²⁺, and ADP/ADPH with Mg²⁺.

2. DFT_calculations: Contains data for the free energy profile of the reaction for the system ADP/ADP with Mg²⁺, using DFT level calculations for the QM region. This folder includes topology, work vs. reaction coordinate, trajectories, and inputs. Both forward and backward reactions are included.

3. Umbrella_Sampling: Contains data for: ADP/ADP with Mg²⁺ and ADP/ADPH without Mg²⁺. Includes topology, free energy profiles built using the WHAM method, trajectories, and reaction coordinate values for each umbrella sampling (US) simulation window.

4. Commitment_Analysis_[part1, part2, and part3]: Contains data for all systems in this folder: ADP/ADP with Mg²⁺ and ADP/ADPH without Mg²⁺. Includes simulation data (topology, inputs, outputs, trajectories) used for the committor plot and commitment analysis. Structures from MSMD forward and backward reactions were used as starting points. Ten replicas were performed for the analysis. The Python scripts for the committor plot and commitment analysis are commitment_plot.py and commitment_analysis.py, respectively.

5. Comparison_structures: Contains transition-state (TS) structures obtained from MSMD and Umbrella Sampling simulations. Also, it contains a script written in R that calculates the PCA  analysis for both sets of TS structures.

The following files in Amber format are provided for each simulation:

• .prmtop: Contains the topological information of the solvated system (e.g., connectivity).
• .nc/.netcdf: Contains the raw trajectory of the simulation (without centering or imaging molecules).
• .rst7: Provides the initial coordinates.
• .RST: Amber restraint file specifying the reaction coordinate and other applied restraints.
• .mdin: Input control data for the simulation (e.g., number of steps, step time, temperature control).
• .dat: Contains the SMD output information along the reaction coordinate (e.g., work, force, reaction coordinate measured on the system).

Further details can be found in the README files within each directory. Below is the abstract of the corresponding study:

"Transition-state theory has provided the theoretical framework to explain the enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles of conformations, unique transition states would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied the nature of the enzymatic transition state for the phosphoryl-transfer step in adenylate kinase by quantum-mechanics/molecular-mechanics calculations. We find a structurally wide set of energetically equivalent configurations that lie along the reaction coordinate and hence a broad transition-state ensemble (TSE). A conformationally delocalized ensemble, including asymmetric transition states, is rooted in the macroscopic nature of the enzyme. The computational results are buttressed by enzyme kinetics experiments that confirm the decrease of the entropy of activation predicted from such wide TSE. Transition-state ensembles as a key for efficient enzyme catalysis further boosts a unifying concept for protein folding and conformational transitions underlying protein function."