Blog 2 – Using Charmm-GUI: Combining Docking, Molecular Dynamics Simulation, and Free Energy Calculation to Improve the Accuracy of Virtual Screening of Anticancer Drug Candidates Against Human Telomeric G-quadruplex DNA

Previous issues that Dr. Deng’s research has encountered include inaccurate 3D visualization of results. This issue is not due to incorrect input or human error, but rather due to the limited abilities/extent of the algorithm in molecular docking programs previously used. To solve this issue, we are currently trying to utilize a different molecular docking program called Charmm-GUI. Charmm-GUI is designed to “interactively build complex systems and prepare their inputs with well-established and reproducible simulation protocols for state-of-the-art biomolecular simulations” (as described by its official website). In coordination with widely used simulation packages such as CHARMM, AMBER, NAMD, GROMACS, GENESIS, LAMMPS, Desmond, and OpenMM, Charmm-GUI is a very promising platform whose more streamlined interface will hopefully provide more accurate results for our virtual screening of anticancer drug candidates against human telomeric G-quadruplex DNA.

Work for this project under Dr. Deng has been going smoothly so far. Regular communication has been crucial, and I am fortunate that Dr. Deng is always available to provide insight and tips in the learning process for this new molecular docking program and the overall problem-solving process. We plan on continuing research during Winter Break going into the Spring Semester, during which we hope to obtain final results.

Blog 1: Combining Docking, Molecular Dynamics Simulation, and Free Energy Calculation to Improve the Accuracy of Virtual Screening of Anticancer Drug Candidates Against Human Telomeric G-quadruplex DNA

In cancer research, the human telomeric G-quadruplex (G4) is a target of great interest and potential for anticancer drugs. At the ends of chromosomes in typical cells, the telomere is a region of repetitive nucleotide sequences that protect chromosomes from degradation and are cleaved little by little after each cell replication. This shortening of the telomere eventually leads to apoptosis (cell death), thus preventing the replication of critically shortened DNA. In the case of cancer, however, this programmed cell death does not occur due to the continuous activity of telomerase which facilitates the maintenance of the telomere lengths. Consequently, cancer cells continue to replicate without degradation and the malignant phenotype is retained. Previous research has shown that targeting the human telomeric G4 in telomeric DNA inhibits telomerase, effectively disrupting this process and disrupting telomere maintenance.

Thus, under the guidance and leadership of Professor Nanjie Deng, the purpose of this research project is to collaboratively improve computational screening of anti-cancer drug candidates binding human telomeric G4. In particular, this entails elucidating the ligand selectivity of protoberberines which have been previously studied to bind to human telomeric G4. Using docking, molecular dynamics simulation, and free energy calculation, we aim to determine which drug molecules have the highest chances of binding success. Final results will be presented at the American Chemical Society national meeting. 

Molecular docking is the process of predicting ligand conformation and orientation within a targeted binding site. Docking aims to find the ideal interaction energy between a specific receptor and ligand in order to create an ideal, stable resulting compound. Within the docking software, one can compare interaction energies of different forms/poses by using the software’s scoring function. For each possible pose, considering all conformational degrees of freedom, the scoring function gives a value that helps the researcher evaluate its affinity. We can increase efficiency by keeping the receptor rigid while keeping the ligand flexible; as a result, possible poses are more limited, and researchers have a narrowed down array of positions to evaluate. In general, this leads to researchers considering the binding energy values among other factors (e.g., enthalpy and entropy). Docking requires a rigorous amount of detail and specificity, however, thus this process can prove to be challenging. My particular role in our research lies in conducting molecular dynamics simulation calculations in order to better observe and analyze binding for data collection.

With our research, we aim to contribute to the worldwide effort of discovering newer and more effective cures for cancer.