Copyright by Matthew Thomas Harger 2019 The Dissertation Committee for Matthew Thomas Harger Certifies that this is the approved version of the following Dissertation. Development and Analysis of Tinker-OpenMM as a GPU-based Free Energy Perturbation Engine Committee: Pengyu Ren, Supervisor Kevin Dalby, Co-Supervisor Ron Elber Walter Fast Karen Vasquez Development and Analysis of Tinker-OpenMM as a GPU-based Free Energy Perturbation Engine by Matthew Thomas Harger Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August 2019 Acknowledgments I want to thank Pengyu Ren and Kevin Dalby, and the members of both labs, as well as the rest of my committee for aiding in my development as a computational chemist. I would especially like to thank Ju-Hyeon Lee, Ramakrishna Edupuganti, and Juliana Taliaferro for their synthetic and assay work that enabled my studies with MELK. I want to thank Peter Eastman for his assistance in learning the OpenMM codebase. His help was invaluable in the early stages of adding free energy perturbation to Tinker-OpenMM Finally, I would like to thank the Jay Ponder lab for useful discussion and assistance in the development of Tinker and Tinker-OpenMM iv Abstract Development and Analysis of Tinker-OpenMM as a GPU-based Free Energy Perturbation Engine Matthew Thomas Harger, PhD The University of Texas at Austin, 2019 Supervisor: Pengyu Ren and Kevin Dalby The utilization of computational technologies for the lead optimization process is one of the biggest challenges in the computational chemistry field. In this dissertation, I describe the addition of GPU-based absolute and relative free energy calculation methods using polarizable force field AMOEBA to Tinker-OpenMM. I then proceed to test the capabilities of this platform by studying the binding free energy and binding structures of derivatives of the MELK inhibitor IN17. Also, I present the implementation of virial- based pressure control to the Tinker-OpenMM platform that is needed for performing isobaric simulations. v Table of Contents INTRODUCTION ............................................................................................................... 1 Docking .......................................................................................................................... 2 Machine Learning ........................................................................................................... 4 Quantum Mechanics ........................................................................................................ 8 Molecular Dynamics ..................................................................................................... 10 Free energy from molecular dynamics simulations ............................................... 12 Forcefields .................................................................................................................... 14 GPU Computing ............................................................................................................ 17 Dissertation Overview ................................................................................................... 19 TINKER-OPENMM: ABSOLUTE AND RELATIVE ALCHEMICAL FREE ENERGIES USING AMOEBA ON GPUS. .............................................................................................. 21 Introductory Statements ................................................................................................ 21 Abstract......................................................................................................................... 22 Introduction................................................................................................................... 23 IMPLEMENTATION DETAILS .................................................................................. 29 Tinker-OpenMM interface .................................................................................... 29 Absolute binding free energy ................................................................................ 29 Dual-topology relative free energy ....................................................................... 32 Methods ........................................................................................................................ 34 Simulation setup ................................................................................................... 34 Molecular dynamics ............................................................................................. 34 vi Bennett acceptance ratio ....................................................................................... 35 Hydration of aromatic compounds ........................................................................ 35 Sampl4 host-guest binding simulations ................................................................. 36 RESULTS ..................................................................................................................... 37 Force Agreement .................................................................................................. 37 Computational efficiency ...................................................................................... 37 GPU/CPU absolute free energy agreement ........................................................... 39 GPU/CPU relative free energy agreement ............................................................. 39 Discussion and Conclusions .......................................................................................... 40 Concluding remarks ...................................................................................................... 41 Tables ........................................................................................................................... 42 Figures .......................................................................................................................... 46 COMPUTATIONAL INSIGHTS INTO THE BINDING OF IN17 INHIBITORS TO MELK ........ 52 Abstract......................................................................................................................... 52 Introductory Statements ................................................................................................ 52 Introduction................................................................................................................... 55 Methods: ....................................................................................................................... 57 Parameterization ................................................................................................... 57 Simulation parameters .......................................................................................... 58 Complex structure generation: .............................................................................. 58 Binding free energy simulations ........................................................................... 59 IN17 Solvent Phase Crystal Structure ................................................................... 60 vii Results/Discussion ........................................................................................................ 61 Aryl-Carbonyl Isomerism ..................................................................................... 61 MELK-nintedanib complex structural prediction .................................................. 61 Absolute binding free energy of MELK with IN17 ............................................... 63 IN17 binding mode ............................................................................................... 64 Relative binding free energy of IN17 derivatives .................................................. 65 The n-terminal loop structure is altered by substitution on the benzene (G2) offshoot .......................................................................................................... 66 Effects of substitution on binding mode ................................................................ 67 Use of restrained equilibration to improve prediction ............................................ 68 Entropy-enthalpy compensation............................................................................ 69 Conclusions................................................................................................................... 71 Acknowledgments ......................................................................................................... 72 Concluding Statements .................................................................................................. 72 Tables ........................................................................................................................... 76 Figures .......................................................................................................................... 78 viii VIRIAL BASED BERENDSEN BAROSTAT ON GPUS USING AMOEBA IN TINKER- OPENMM ............................................................................................................... 86 Introductory Statements ................................................................................................ 86 Introduction: ................................................................................................................. 86 Methods: ......................................................................................................................