qmld Workflow

Quantum Mechanics Lambda Dynamics (QMLD) serves as a pipeline for lambda-scaled QM/MM calculations.

1. MSLD Sampling (CHARMM)

---

Run the initial Multi-Site Lambda Dynamics (MSLD) simulation within CHARMM. This step generates the conformational ensemble required for subsequent QM/MM refinement.

Output:

• Trajectory files: .dcd
• Lambda log files: .lmd

2. Trajectory Processing & Filtering

---

Before QM refinement, the raw trajectory must be filtered for "physical" states where the alchemical transition is complete.

A. Lambda Filtering

• Parse the .lmd files.
• Retain only the frames where $\lambda$ > 0.99 for all active sites.
• This ensures the system is in a discrete physical state rather than an intermediate hybrid state.

B. PDB Generation

• Use the MMTSB Toolset to extract specific frames from the .dcd file corresponding to the filtered timestamps.
• Convert the binary trajectory into a series of PDB files for structural analysis.

3. QM Region Definition & Input Preparation

---

Define the subset of atoms to be treated at the QM level.

• Selection: Identify residues/atoms for the QM region (e.g., a ligand and nearby catalytic residues).

• Protonation & Capping: If the QM/MM boundary bisects a covalent bond, the software will automatically:

  • Truncate the bond.
  • Add a Link Atom (typically hydrogen) to satisfy the valence of the QM atom.

• Input Generation: The script generates:

  • Q-Chem input specifying the basis set, functional, and external point charges.
  • CHARMM input for calculating the MM-level energy of the same configuration.

4. Single Point Calculations (Q-Chem & CHARMM)

---

The software executes Q-Chem to calculate the electronic energy ($E_{QM}$) & CHARMM ($E_{MM}$) of the defined region.

5. Data Aggregation & $\Delta G$ Calculation

---

Upon successful completion of all single-point runs, the software parses the output to calculate the Composite Free Energy ($\Delta G_{comp}$):

$$\Delta G_{comp} = \langle E_{QM} - E_{MM} \rangle + \Delta G_{MSLD} $$

Data Archiving:

• All intermediate results and energy logs are saved in the results/ directory for final statistical analysis.