Alchemical Transformation: Building Into Architecture

Good buildings like good pictures not only engage our eyes but also our mind. It is through the connection of sensory experience to thought, that craft is transformed into art, and building into architecture

Comment on "Deficiencies in molecular dynamics simulation-based prediction of protein-DNA binding free energy landscapes"

Sequence-specific DNA binding transcription factors play an essential role in the transcriptional regulation of all organisms. The development of reliable in silico methods to predict the binding affinity landscapes of transcription factors thus promises to provide rapid screening of transcription factor specificities and, at the same time, yield valuable insight into the atomistic details of the interactions driving those specificities. Recent literature has reported highly discrepant results on the current ability of state-of-the-art atomistic molecular dynamics simulations to reproduce experimental binding free energy landscapes for transcription factors. Here, we resolve one important discrepancy by noting that in the case of alchemical free energy calculations involving base pair mutations, a common convention used in improving end point convergence of mixed potentials in fact can lead to erroneous results. The underlying cause for inaccurate double free energy difference estimates is specific to the particular implementation of the alchemical transformation protocol. Using the Gromacs simulation package, which is not affected by this issue, we obtain free energy landscapes in agreement with the experimental measurements; equivalent results are obtained for a small set of test cases with a modified version of the AMBER package. Our findings provide a consistent and optimistic outlook on the current state of prediction of protein-DNA binding free energy interactions using molecular dynamics simulations and an important precaution for appropriate end point handling in a broad range of free energy calculations

Alchemical Transformation: Consciousness and matter, form and information

There has grown up, relatively recently, a nucleus of interests called ìconsciousness studiesî in which physicists and mathematicians, as well as neuroscientists and psychologists, attempt to discover the origins of ìconsciousnessî within the brain. A variety of approaches are employed, some based upon neural networks, others that argue that consciousness must have a quantum mechanical basis, or involve self-organization arising out of non-linearity. A common thread is a certain sense of optimism that ìthe question of consciousnessî will yield its secrets in the same way as, for example, the genetic code or sub-atomic matter. I must confess that I find none of the approaches or arguments particularly convincing. It could be soî, I find myself thinking, but it could equally be otherwise.î My greatest concern is that old habits of thinking and ways of seeing, which could, in part, be termed mechanistic or reductionist abound in this new field, a field, I believe, that is radically different from anything science has hitherto explored. There are deep philosophical problems still to be debated, issues involving questions of identity, the role of the observer, the movement from object to process, the role of the subtle and the transformation of matter by what may lie beyond. We must move cautiously. The issue is informed from several different sources. There is the subjective, which can be perfectly rational and, in a cer tain sense, scientific. The subjective includes knowledge and approaches from the personal, the psychotherapeutic and various meditative and mystical traditions. Then there is our increasing scientific knowledge of the brain\u27s structure and chemistry, as well as the similarity of certain neurotransmitters to molecules employed by the immune system, which, distributed throughout the body, may well be as complex and equally subtle as the brain itself. Speculations about consciousness, non-locality, subtle levels of matter and active information also come from theoretical physics. Such an influx of creativity, from the theoretical sciences, is to be welcomed yet there is a danger of a certain naivetÈ capable of glossing over much deeper issues. To this list of sources I would add the philosophical tradition, of West and East, instruments of investigation that are sometimes ignored by scientists working in the field. Anyone speaking about consciousness , for example, should be cautioned by Wittgenstein\u27s writings on language games. Indeed, language is one of the key issues in our whole venture. Having had the privilege of discussions with Native American elders who speak the Algonquin family of languagesóall strongly verb-basedóI realize how deeply conditioned is our thinking by noun-based Indo- European languages. Our acts of speech incline us to perceive a world of objects and of concepts. The creation of the concept, placing a boundary around thoughts, ordering them into classes, and classes of classes, seems inevitable to us and the very basis of our logical thought. It is therefore salutary to realize that an equally rational and deeply philosophical people do not involve themselves with the creation of concepts but base their thinking on process, transformation and flux. Were a Blackfoot to write an essay on the subject of ìconsciousness (of course this concept itself would never arise) many of the problems that currently face us-would never arise; a different set of difficulties could, to us, be particularly illuminating. in particular, since group consciousness, shared dreams, constant transformation, and participation in a world of ìenergies or ìspirits,î seems perfectly natural, Blackfoot philosophers may be less interested in ìcollective mindî that in speculating as how such a thing as an individual consciousness and a fixed ego could ever emerge out of such a flux. In engaging in these investigations we should keep Niels Bohrís maxim before us, ìWe are suspended in language in such a way that we cannot say what is up and what is down. We must never forget that ìrealityî too is a human word just like ìwave\u27 or ìconsciousnessî. Our task is to learn to use these words correctly.

In silico screening of drug-membrane thermodynamics reveals linear relations between bulk partitioning and the potential of mean force

The partitioning of small molecules in cell membranes---a key parameter for pharmaceutical applications---typically relies on experimentally-available bulk partitioning coefficients. Computer simulations provide a structural resolution of the insertion thermodynamics via the potential of mean force, but require significant sampling at the atomistic level. Here, we introduce high-throughput coarse-grained molecular dynamics simulations to screen thermodynamic properties. This application of physics based models in a large-scale study of small molecules establishes linear relationships between partitioning coefficients and key features of the potential of mean force. This allows us to predict the structure of the insertion from bulk experimental measurements for more than 400,000 compounds. The potential of mean force hereby becomes an easily accessible quantity---already recognized for its high predictability of certain properties, e.g., passive permeation. Further, we demonstrate how coarse graining helps reduce the size of chemical space, enabling a hierarchical approach to screening small molecules.Comment: 8 pages, 6 figures. Typos fixed, minor correction

Performance and Analysis of the Alchemical Transfer Method for Binding Free Energy Predictions of Diverse Ligands

The Alchemical Transfer Method (ATM) is herein validated against the relative binding free energies of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM software to compute the relative binding free energies (RBFE) of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical relative binding free energy methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and post-corrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 relative binding free energy calculations for eight protein targets and found that ATM achieves accuracy comparable to existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM is applicable as a production tool for relative binding free energy (RBFE) predictions across a wide range of perturbation types within a unified, open-source framework

Statistical thermodynamic basis in drug-receptor interactions: double annihilation and double decoupling alchemical theories, revisited

Alchemical theory is emerging as a promising tool in the context of molecular dynamics simulations for drug discovery projects. In this theoretical contribution, I revisit the statistical mechanics foundation of non covalent interactions in drug-receptor systems, providing a unifying treatment that encompasses the most important variants in the alchemical approaches, from the seminal Double Annihilation Method by Jorgensen and Ravimohan [W.L. Jorgensen and C. Ravimohan, J. Chem. Phys. 83,3050, 1985], to the Gilson's Double Decoupling Method [M. K. Gilson and J. A. Given and B. L. Bush and J. A. McCammon, Biophys. J. 72, 1047 1997] and the Deng and Roux alchemical theory [Y. Deng and B. Roux, J. Chem. Theory Comput., 2, 1255 2006]. Connections and differences between the various alchemical approaches are highlighted and discussed, and finally placed into the broader context of nonequilibrium thermodynamics.Comment: 25 pages, 4 figure