RevTS

Documentation Index

Fetch the complete documentation index at: https://docs.revilico.bio/llms.txt

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Why Use This Engine?

In the documentation below, we will use Revilico’s RevTS engine to locate and characterize transition states for chemical reactions involving small molecules or reactions occurring within protein binding sites. RevTS predicts the activation barrier (DG double-dagger) and reaction energy (DG) using a multi-stage pipeline that combines fast semiempirical nudged elastic band calculations for an initial pathway guess with DFT saddle-point optimization, frequency analysis, and intrinsic reaction coordinate (IRC) following for full characterization at the wB97M-V/def2-TZVP level. The resulting energetics are directly comparable to RevQS binding scores, enabling a unified quantum mechanical picture of both ground-state binding and reactive transformation within the same target.

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Background

A transition state (TS) is the highest-energy point on the minimum energy path connecting reactants to products. It corresponds to a first-order saddle point on the potential energy surface: a maximum along the reaction coordinate and a minimum in all other directions. Characterizing the TS provides the activation barrier DG double-dagger, which determines the rate of the reaction through the Arrhenius and Eyring equations, and the reaction energy DG, which determines thermodynamic favorability. In drug discovery, transition state analysis is relevant to understanding metabolic reactions, covalent inhibitor mechanisms, enzymatic reaction barriers, and the kinetics of drug-induced conformational changes. RevTS uses xTB for fast semiempirical path generation, Psi4 for high-quality saddle-point optimization and IRC, and PySCF (the same engine as RevQS) for the final energy evaluation at wB97M-V/def2-TZVP, ensuring that binding energies and reaction barriers are computed at a consistent level of theory.

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Pipeline

Stage 1: NEB Pathway Generation A nudged elastic band (NEB) calculation at the GFN2-xTB semiempirical level generates an initial estimate of the reaction path and transition state geometry. NEB constructs a chain of 8 molecular images connecting the reactant and product geometries, connected by spring forces that maintain equal spacing along the path while allowing each image to relax toward the minimum energy path. The spring potential is: $$V_{\text{spring}} = \frac{k_{\text{spring}}}{2}(|\mathbf{R}_{i+1} - \mathbf{R}_i| - |\mathbf{R}_i - \mathbf{R}_{i-1}|)^2$$ With a default spring constant of 0.02 Eh/Bohr-squared. The highest-energy image along the NEB path serves as the initial TS guess for the DFT optimization. If xTB is unavailable, a linear interpolation of the Cartesian coordinates between reactant and product is used as the fallback starting path. Stage 2: DFT Saddle-Point Optimization The xTB TS guess is refined to a true first-order saddle point using the P-RFO (Partitioned Rational Function Optimization) algorithm in Psi4. P-RFO partitions the Hessian eigenvectors into a reaction mode (maximized) and all orthogonal modes (minimized), ensuring convergence to the correct saddle point rather than drifting toward a higher-order critical point or a minimum. The optimization uses wB97M-D3BJ/def2-SVP (Psi4 uses the D3BJ empirical dispersion variant of wB97M because Psi4 does not natively implement VV10 non-local correlation). Geometric differences between the D3BJ and full VV10 variants are below 0.3 degrees in angles and 0.005 Angstroms in bond lengths for typical organic reactions, making this combination appropriate for geometry optimization. In binding-site mode, protein atoms outside the reactive region are frozen, allowing only the ligand and the immediately surrounding residue atoms to relax during the optimization. Stage 3: Frequency Analysis At the converged saddle point geometry, analytic second derivatives are computed to obtain the harmonic vibrational frequencies. A valid transition state has exactly one imaginary frequency (reported in cm-1 as a negative number by convention), corresponding to the normal mode that connects reactants to products along the reaction coordinate. Frequencies are scaled by a factor of 0.97 to correct for systematic overestimation of harmonic force constants. The zero-point energy correction to the barrier is extracted from the real frequencies. Stage 4: IRC Following The intrinsic reaction coordinate (IRC) confirms that the TS connects the intended reactants and products. Starting from the TS geometry and following the mass-weighted gradient in both directions using the Gonzalez-Schlegel second-order (GS2) method: $$\mathbf{R}(s + \delta s) = \mathbf{R}(s) - \delta s \frac{\mathbf{g}(s)}{|\mathbf{g}(s)|}$$ Where the step is taken in mass-weighted Cartesian coordinates with step size 0.1 Bohr times amu to the one-half. The IRC terminates when the gradient falls below the convergence threshold, confirming that each direction leads to a proper minimum. If Psi4 is unavailable, a first-order Euler predictor IRC in PySCF provides the same confirmation at reduced accuracy. Stage 5: High-Level Single-Point Energy The final energetics are computed at the wB97M-V/def2-TZVP level using PySCF with GPU4PySCF acceleration, the same method as RevQS. For binding-site calculations, the Boys-Bernardi counterpoise correction is applied. The activation barrier and reaction energy are then: $$\Delta G^{\ddagger} = E(\text{TS, wB97M-V/TZVP}) - E(\text{reactant, wB97M-V/TZVP}) + \Delta E_{\text{ZPE}} + \Delta E_{\text{CP}}$$ $$\Delta G = E(\text{product, wB97M-V/TZVP}) - E(\text{reactant, wB97M-V/TZVP})$$ Wigner Tunneling Correction For reactions involving hydrogen transfer, quantum tunneling can significantly enhance the reaction rate beyond the classical Arrhenius contribution. The Wigner correction factor is: $$\kappa_W = 1 + \frac{1}{24}\left(\frac{h\nu^{\ddagger}}{k_BT}\right)^2$$ Where $\nu^{\ddagger}$ is the magnitude of the imaginary frequency, $h$ is Planck’s constant, and $k_B$ is the Boltzmann constant at 298.15 K. The effective rate constant is multiplied by $\kappa_W$.

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Running the Engine

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Inputs

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Outputs

• DG double-dagger: Activation barrier in kcal/mol with ZPE and CP corrections
• DG reaction: Reaction energy in kcal/mol
• Wigner kappa: Tunneling correction factor
• TS confirmation: Whether a single imaginary frequency was found and IRC connected endpoints
• Imaginary frequency: Transition state normal mode frequency in cm-1
• IRC profile: Energy vs. reaction coordinate plot from TS to reactant and product
• Per-residue decomposition: Interaction contributions in binding-site mode
• TS geometry file: Optimized transition state structure in XYZ format
• Method string: Full description of the computational protocol applied