Efficient Biomolecular Computations Towards Applications in Drug Discovery

Atomistic modeling and simulation methods facilitate biomedical research from many respects, including structure-based drug design. The ability of these methods to address biologically relevant problems is largely determined by the accuracy of the treatment of complex solvation effects in target biomolecules surrounded by water. The implicit solvent model – which treats solvent as a continuum with the dielectric and non-polar properties of water – offers a good balance between accuracy and speed. Simple and efficient, generalized Born (GB) model has become a widely used implicit solvent responsible for the estimation of key electrostatic interactions. The main goal of this research is to improve the accuracy of protein-ligand binding calculations in the implicit solvent framework. To address the problem (1) GBNSR6, an accurate yet efficient flavor of GB, has been thoroughly explored in the context of protein-ligand binding, (2) a global multidimensional optimization pipeline is developed to find the optimal dielectric boundary made of atomic and water probe radii specifically for protein-ligand binding calculations using GBNSR6. The pipeline includes (3) two novel post-processing steps for optimum robustness analysis and optimization landscape visualization. In the final step of this research, (4) accuracy gain the optimal dielectric boundary can bring in practice is explored on binding benchmarks, including the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Computer Science and Applications

Department dc:contributor.department

Computer Science

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2020

Author dc:creator

• Forouzesh, Negin

Chair dc:contributor.committeechair

• Onufriev, Alexey

Committee members dc:contributor.committeemember

• Zhang, Liqing
• Raghvendra, Sharath
• Bevan, David R.
• Gohlke, Holger

• Free Energy Calculation
• Molecular Simulation
• Drug Discovery

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:26933

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/107266