Free Energy Methods Involving Quantum

Free Energy Methods Involving Quantum
Physics, Path Integrals, and Virtual Screenings

Development, Implementation and Application in Drug Discovery


This thesis was created within the graduate programs of the Berlin Mathematical

School (BMS) and the International Max Planck Research School for Compu-tational Biology and Scientific Computing (IMPRS-CBSC) of the Max Planck

Institute for Molecular Genetics (MPIMG), as well as within the Department of Mathematics and Computer Science and the Department of Physics of the Freie Universität Berlin.

Download: Free Energy Methods Involving Quantum


Abstract
Computational science has the potential to solve most of the problems which pharma-
ceutical research is facing these days. In this field the most pivotal property is arguably the free energy of binding. Yet methods to predict this quantity with sufficient accuracy,
reliability and efficiency remain elusive, and are thus not yet able to replace experimental
determinations, which remains one of the unattained holy grails of computer-aided
drug design (CADD). The situation is similar for methods which are used to identify
promising new drug candidates with high binding affinity, which resembles a closely
related endeavor in this field.
In this thesis the development of a new free energy method (QSTAR) was in the focus.
It is able to explicitly take into account the quantum nature of atomic nuclei which so far
was not done in binding free energy simulations of biomolecular systems. However, it can
be expected to play a substantial role in such systems in particular due to the abundance
of hydrogen atoms which posses one of the strongest nuclear delocalizations of all atoms.
To take these nuclear quantum effects into account Feynman’s path integral formulation
is used and combined in a synergistic way with a novel alchemical transformation scheme.
QSTAR makes also available the first readily available single topology approach for
electronic structure methods (ESMs). Moreover, an extended alchemical scheme for
relative binding free energies was developed to address van der Waals endpoint problems.
QSTAR and the alchemical schemes were implemented in HyperQ, a new free energy
simulation suite which is highly automated and scalable.
Most ESMs methods become soon prohibitively expensive with the size of the system,
a restriction which can be circumvented by quantum mechanics/molecular mechanics
(QM/MM) methods. In order to be able to apply QSTAR together with ESMs on
biomolecular systems an enhanced QM/MM scheme was developed. It is a method for
diffusive systems based on restraining potentials, and allows to define QM regions of
customizable shape while being computationally fast. It was implemented in a novel
client for i-PI, and together with HyperQ allows to carry out free energy simulations
of biomolecular systems with potentials of very high accuracy.
One of the most promising ways to identify new hit compounds in CADD is provided
by structure-based virtual screenings (SBVSs) which make use of free energy methods.
In this thesis it is argued that the larger the scale of virtual screenings the higher their
success. And a novel workflow system was developed called Virtual Flow, allowing
to carry out SBVS-related tasks on computer clusters with virtually perfect scaling
behavior and no practically relevant bounds regarding the number of nodes/CPUs. Two
versions were implemented, VFLP and VFVS, dedicated to the preparation of large
ligand databases and for carrying out the SBVS procedure itself.
As a primary application of the new methods and software a dedicated drug design
project was started involving three regions on the novel target EBP1, expected to be
located on protein-protein interfaces which are extremely challenging to inhibit. Three
multistage SBVSs were carried out each involving more than 100 million compounds.
Subsequent experimental binding assays indicated a remarkably high true hit rate of above
30 %. Subsequent fluorescence microscopy of one selected compound exhibited favorable
biological activities in cancer cells. Other applied projects included computational hit
and lead discovery for several other types of anti-cancer drugs, anti-Herpes medications,
as well as antibacterials.


Acknowledgements

Each one of us can make a difference. Together we make change.
Barbara Mikulski

There are many people who have supported my doctoral research in one way or
another, and I am more than grateful to all of them.
At first I would like to sincerely thank the person who made this PhD project
possible, my supervisor Christof Schütte. On the one hand he provided what was most
important to me: Freedom. Freedom to choose and design the contents of my PhD, and
freedom to find and follow my own paths. This freedom transformed my PhD into a
wonderful adventure within the realm of science. On the other hand, during this journey
Christof Schütte provided me with all the support required whenever there was a need.
I am also deeply grateful to my two mentors/thesis advisors, Petra and Max, for
their constant support, their exceptional kindness, and the trust they seemed to have
in me from the early days on. I feel more than fortunate to having had them as my
mentors, and it was a true pleasure to work with them. To Noemi, my mentor of the
Berlin Mathematical School (BMS), I am also grateful for her advices on several matters.

A substantial part of this work would not have been possible without all the collabo-
rating groups and people involved, and I would like to sincerely thank all of them for

their efforts. Among them are Haribabu Arthanari and Gerhard Wagner of the Dana
Farber Cancer Institute and the Harvard Medical School for their support in bringing
my applied project to the experimental level, and for having invited me to visit their
research groups. I am thankful to Andras Boeszoermenyi, my primary coworker in
Boston regarding the experimental work, for all his time and the interesting discussion
during my visit. And to our collaborators, Nancy Kedersha and Pavel Ivanov in the
Brigham and Women’s Hospital in Boston, who have done excellent work in regard
to the fluorescence microscopy experiments. Magdalena Czuban from the Charité in
Berlin I would like to thank for having worked with me on our new collaborative project,
Michelle Ceriotti as well as Riccardo Petraglia from the EPFL for their support in
relation to i-PI/i-QI, and Jonathan LaRochelle, as well as a few members of the Naar
Lab and the Coen Lab with whom I had the joy to work with in several collaborative
projects. I would also like to acknowledge Enamine, in particular Olga Tarhanova, for
having supported my applied drug discovery project by freely synthesizing compounds
for us from their vast virtual compound libraries.

Also, it was a true pleasure to having had such wonderful colleagues and fellow stu-
dents in the Computational Biophysics Group, the Biocomputing Group, the Arthanari

Lab, the Wagner Lab, the Berlin Mathematical School (BMS) and the International Max

Planck Research School for Computational Biology and Scientific Computing (IMPRS-
CBSC). Thank you all for having provided such a pleasant and supportive working

environment.
To my friends Moritz and Brigitte I would like to express my gratitude for reading
my thesis and their valuable comments, Moritz also for his support regarding Python,
and Brigitte for being so meticulous in her reading and encouraging. Also Gerhard
König and Han Cheng Lie I would like to thank for various discussions.

Among the administrative staff of the research groups and graduate schools I would
like to thank in particular Fabian Feutlinske, Kirsten Kelleher, Chris Seyffer, Benita
Ross, Dominique Schneider, Tanja Fagel, Annette Schumann-Welde, and Dorothé Auth
for their constant and kind support throughout my PhD.
Considerable computational resources were required during this PhD, and I would
like to thank all the sources which have granted me computing time and additional
technical support. Among the high performance computers used are the Sheldon, Yoshi,
and Soroban Linux clusters of the Freie Universität Berlin, the HLRN III supercomputer
in Berlin/Hanover, the ERISOne cluster of Partners Healthcare/Dana Farber Cancer
Institute, the Orchestra and O2 clusters of the Harvard Medical School, the Coral cluster
of the Wagner Lab in the Harvard Medical School, and the Odyssey cluster of the Faculty
of Harvard University. Among the technical and scientific staff related to these resources
I would like to thank in particular Jens Dreger, Christian Tuma, Guido Laubender,
Francesco Pontiggia, James Cuff and Scott Yockel for their support in various ways.
I would also like to acknowledge the free and open source software communities
which provide the world altruistically with such magnificent and versatile software, but
which we often take for granted. Their contributions played a crucial role in various
aspects of this work, and using their packages has often been a delight.
This work was funded by several institutions/groups (mainly via scholarships or
traveling allowances), and I would like to thank all of them for their support. These are the
Einstein Center of Mathematics Berlin/BMS, the Computational Biophysics Group/Freie
Universität Berlin, the IMPRS-CBSC/Max Planck Institute for Molecular Genetics, the
Arthanari Lab/Dana Farber Cancer Institute, and the Schneider Group/Berlin Institute
of Technology.

Learn more: A Practical Guide to ‘Free-Energy’ Devices

Practical guide
✰* Revealed At Last: Ancient Invention Generates Energy-On-Demand
The design includes:

• Harnessing electricity from the Earth: Neither is Schumann Resonance, nor is it known by Electromagnetism. It's The Sea of Energy in Which the Earth Floats
• Extract from ordinary electricity by the method called “fractionation.”
• Reverse Tesla coil - "Back to Back" mechanism
• Combination of radiant energy and negative resistance to amplify electricity 
• Nikola Tesla’s method of magnifying electric power by neutralizing the magnetic counter-forces in an electric generator

Note:

1. As early as 1904, Nicola Tesla, experimenting with AC currents of high potential and high frequency, said: "Ere many generations pass, our machinery will be driven by a power obtainable at any point in the universe... Throughout space there is energy. Is this energy static or kinetic? If static, our hopes are in vain; if kinetic --- and this we know it is for certain --- then it is a mere question of time when men will succeed in attaching their machinery to the very wheelwork of nature."

2. Harnessing cosmic energy is the most practical method yet discovered by man. Furthermore, it is possible to utilize this vast source of energy from the universe without a prime mover at any point on the earth --- on the ground, in the air, on the water, under the water, or even underground. If one considers that an electrical generator is not in the true sense a generator --- as electricity is not made by the generator --- but is merely an electrical pump, the Moray Radiant Energy device may then be referred to as a cosmic ray pump: that is, a high speed electron oscillator serving as a detector of cosmic radiations which causes a pumping action or surging within its circuitry.