Sensitivity in Binding Free Energies Due to Protein Reorganization

• DOI: 10.1021/acs.jctc.6b00532
• Publication Date: 2016-07-27T19:02:46Z
• Authors: Nathan M. Lim; Lingle Wang; Robert Abel; David L. Mobley
• Keywords: 0301 basic medicine; Protein Structure; 612; Molecular Dynamics Simulation; Ligands; 01 natural sciences; Computer Software; Medicinal and Biomolecular Chemistry; 03 medical and health sciences; Theoretical and Computational Chemistry; Theoretical and computational chemistry; 0103 physical sciences; Site-Directed; Chemical Physics; Binding Sites; Protein Structure, Tertiary; Physical chemistry; Mutagenesis; Chemical Sciences; Mutagenesis, Site-Directed; Thermodynamics; Muramidase; Generic health relevance; Biochemistry and Cell Biology; Tertiary; Algorithms; Protein Binding

Tremendous recent improvements in computer hardware, coupled with advances sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used aid pharmaceutical drug discovery projects. However, despite these innovations, there still needs for further improvement algorithms more adequately sample protein motion relevant binding. Here, we report our work identifying studying such clear remaining the apolar cavity of T4 lysozyme L99A. In this study, model experimental results that show progressive opening pocket response a series homologous ligands.1 Even while using enhanced techniques, demonstrate predicted relative energies (RBFE) sensitive initial conformational state. Particularly, highlight importance sufficient changes how inclusion three key residues "hot" region FEP/REST simulation improves resolves sensitivity, given enough time.