Let's discuss Glide (Grid-based ligand docking with energetics) module of Schrodinger!!

A general protocol for ligand docking using Glide:

Preparation of receptor and ligand structures: The receptor structure should be prepared by adding missing atoms, assigning charges, and optimizing the geometry. The ligand structure should be prepared by generating multiple conformations and assigning charges.

Generation of the receptor grid: Glide generates a grid that represents the receptor binding site. The grid is generated by defining the dimensions of the binding site, assigning van der Waals and electrostatic interaction potentials to the grid points, and scaling and translating the receptor structure to fit the grid.

Ligand docking: Glide docks the ligand onto the receptor grid by generating and evaluating different ligand conformations and orientations. Glide uses a Monte Carlo algorithm to sample the conformational space and evaluate the fitness of each pose based on a scoring function.

Post-docking analysis: After docking, Glide generates a list of ligand poses ranked by their docking scores. The poses can be visualized and analyzed to identify the best candidates for further study.

The algorithm underlying Glide's ligand docking protocol combines a number of techniques to achieve high accuracy and efficiency. These include:

Grid-based docking: Glide uses a three-dimensional grid to represent the receptor binding site, which allows for efficient sampling of the conformational space and evaluation of different ligand poses.

Ligand-based docking: Glide generates candidate ligand poses by matching the ligand to a library of known conformations and modifying these conformations to generate new poses. This allows for efficient sampling of ligand conformations and orientations.

Scoring function: Glide uses a sophisticated scoring function that takes into account both the ligand-receptor interaction energy and the ligand strain energy. The scoring function also includes terms to account for desolvation and entropy effects.

Protein flexibility: Glide allows for protein flexibility by incorporating a flexible receptor model that can accommodate ligand-induced conformational changes.

Overall, Glide's ligand docking protocol is a powerful tool for predicting ligand binding modes and affinities, and can be applied to a wide range of drug discovery applications.

Question: what is the monte carlo algorithm here

Answer: In the context of Glide's ligand docking protocol, the Monte Carlo algorithm is used to sample the conformational space of the ligand in order to find the best docking pose.

The Monte Carlo algorithm is a stochastic method that uses a series of random moves to explore the conformational space of the ligand. During each iteration of the algorithm, a random move is proposed, such as a rotation or translation of the ligand. The proposed move is then evaluated based on the change in the scoring function, and either accepted or rejected based on a probability calculated using the Metropolis criterion.

The Metropolis criterion is a rule for accepting or rejecting a proposed move based on the change in energy and a parameter called the temperature. At high temperatures, the algorithm is more likely to accept moves that increase the energy, allowing it to explore a wider range of conformational space. As the temperature is decreased, the algorithm becomes more selective, accepting only moves that lead to lower energy conformations.

The Monte Carlo algorithm is used in Glide to explore the conformational space of the ligand and identify the best docking pose based on the scoring function. By using a stochastic approach, the algorithm is able to efficiently search through a large number of possible ligand conformations and identify the most favorable binding mode.

Question: What are the Glide docking score and docking energy?

Answer: The Glide docking score is a weighted sum of different terms that represent the energy of the ligand-receptor interaction and the strain energy of the ligand. The exact formula for the Glide docking score is proprietary and not publicly disclosed. However, the score can be broken down into several terms that are commonly used in molecular docking:

• van der Waals energy: This term represents the attractive and repulsive forces between the atoms in the ligand and the receptor. It is calculated using a Lennard-Jones potential and is proportional to the inverse sixth power of the distance between the atoms.
• Electrostatic energy: This term represents the electrostatic interaction between the charged atoms in the ligand and the receptor. It is calculated using Coulomb's law and is proportional to the product of the charges and the inverse distance between the atoms.
• Hydrogen bonding energy: This term represents the energy of the hydrogen bonds formed between the ligand and the receptor. It is calculated based on the distance and orientation of the hydrogen bond acceptor and donor groups.
• Penalty for unsatisfied hydrogen bond donors/acceptors: This term penalizes the ligand for having unsatisfied hydrogen bond donors or acceptors. It is calculated based on the number of unsatisfied hydrogen bond groups and a penalty function.
• Torsional strain energy: This term represents the energy required to rotate the ligand around its bonds. It is calculated based on the torsion angles of the ligand and a penalty function.

The docking energy is another parameter used in molecular docking that represents the energy of the ligand-receptor interaction in a given pose. It is calculated as the sum of the van der Waals and electrostatic energies between the ligand and the receptor. The docking energy is a useful parameter for comparing different docking poses and selecting the most favorable binding mode. However, it does not take into account the strain energy of the ligand, which can be an important factor in ligand binding. The Glide docking score combines the docking energy with additional terms that account for the ligand strain energy and other factors to provide a more accurate assessment of ligand binding.

Question: what is ligand strain energy

Answer: Ligand strain energy refers to the energy required to deform a ligand from its ideal conformation to the conformation it adopts in the binding site of a protein or receptor. It represents the deviation of the ligand from its most stable and energetically favorable conformation, and can contribute significantly to the overall energy of the ligand-receptor interaction. Ligand strain energy arises from the distortion of bond angles, bond lengths, and torsion angles in the ligand due to steric clashes with the protein or receptor, as well as other unfavorable interactions such as electrostatic repulsion or van der Waals clashes. When a ligand binds to a receptor, it undergoes conformational changes to fit into the binding site and form a stable complex. However, these conformational changes may cause the ligand to adopt a conformation that is not its most stable or energetically favorable. This can result in strain energy, which may reduce the overall binding affinity of the ligand for the receptor.

In molecular docking simulations, it is important to account for ligand strain energy in the scoring function, as ligands with high strain energy may not bind well to the receptor, even if their other interactions are favorable. Glide accounts for ligand strain energy in its docking score by including terms that penalize conformational strain, such as torsional strain energy, as well as other factors such as ligand desolvation energy and penalty terms for unsatisfied hydrogen bond donors/acceptors.

Question: Why does the ligands with high or good docking scores have poor Prime MM-GBSA energies

Answer: The Glide docking score and Prime MM-GBSA energy are two different scoring functions that evaluate the binding affinity of a ligand to a receptor. While the Glide docking score is based on empirical scoring functions and is used to rank ligand poses generated during docking, the Prime MM-GBSA energy is based on molecular mechanics and thermodynamics and is used to estimate the free energy of binding of a ligand to a receptor.

There can be several reasons why a ligand with a high Glide docking score may have poor Prime MM-GBSA energy:

• Overfitting: The Glide scoring function is based on a training set of ligand-receptor complexes, and it may be prone to overfitting, where it assigns high scores to ligands that are similar to the training set but not necessarily to the actual ligand-receptor complex. In contrast, the Prime MM-GBSA energy is based on molecular mechanics and thermodynamics and is less prone to overfitting.
• Ligand conformation: The Glide docking score is based on the conformation of the ligand in the binding site, which may not necessarily be the most stable or energetically favorable conformation. In contrast, the Prime MM-GBSA energy considers the free energy of the ligand in solution and in the binding site, and takes into account the entropic and enthalpic contributions to the binding energy.
• Inaccurate force field: The accuracy of the Prime MM-GBSA energy calculation depends on the accuracy of the force field used, which may not be suitable for all ligand-receptor complexes. The force field may not capture all the relevant interactions between the ligand and the receptor, such as protein-ligand hydrogen bonds, solvation effects, or conformational changes induced by ligand binding.

Therefore, a ligand with a high or good docking score may have a poor Prime MM-GBSA energy if the docking score is based on empirical scoring functions, if the ligand conformation is not the most stable or energetically favorable, or if the force field used for the Prime MM-GBSA energy calculation is inaccurate or not suitable for the ligand-receptor complex.