David R. Glowacki’s research while affiliated with University of Bristol and other places

Introduction. Being diagnosed with a life-threatening illness (LTI) is often accompanied by feelings of fear, uncertainty, and loneliness that can severely impact mental health. Relatively few interventions are available to address the existential concerns of individuals facing LTI, while treatment of the underlying physical ailment typically remains the priority of the healthcare system. Research has shown that psychedelic-assisted psychotherapy (PAT) holds promise for supporting mental health in people with LTIs. However, PAT’s potential in this population remains curtailed by several limitations, including regulatory and accessibility issues. Novel approaches that could provide some of the benefits of psychedelic experiences, while avoiding associated challenges, would therefore be highly desirable for supporting the mental well-being of people with LTIs. Among such interventions, VR-based experiences have been suggested as a promising candidate. We here evaluate a program that includes weakly representational, multi-user VR experiences based on a design aesthetic previously described as “numadelic”, which has been demonstrated to elicit self-transcendent experiences comparable to psychedelics.Methods. A prospective cohort study design was used to assess the effects of “Clear Light” (CL) a group-based, 6-session multimedia program that included VR experiences, video calls, and text chats spanning 3 weeks. Participants were individuals suffering from LTIs that self-selected to participate in the CL program. A total of N=15 participants were evaluated based on assessments one week before and after the program, using self-report measures of anxiety, depression, well-being, and secondary psychological outcomes. Results. The intervention was well-tolerated among participants. Significant improvements with moderate effect sizes were observed on self-reported measures of anxiety, depression, and well-being. Secondary measures assessing demoralization, connectedness, and spiritual well-being also showed significant improvements. Discussion. This observational study demonstrated the feasibility and potential benefits of a group-based VR program that can be delivered at-home to people suffering from LTIs. While conclusions are presently limited by the lack of randomization or a comparison group, our findings strongly suggest further research is warranted, including randomized controlled trials.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

Molecular dynamics (MD) simulations provide crucial insight into molecular interactions and biomolecular function. With interactive MD simulations in VR (iMD-VR), chemists can now interact with these molecular simulations in real-time. Our sense of touch is essential for exploring the properties of physical objects, but recreating this sensory experience for virtual objects poses challenges. Furthermore, employing haptics in the context of molecular simulation is especially difficult since \textit{we do not know what molecules actually feel like}. In this paper, we build upon previous work that demonstrated how VR-users can distinguish properties of molecules without haptic feedback. We present the results of a gamified two-alternative forced choice (2AFC) psychophysics user study in which we quantify the threshold at which iMD-VR users can differentiate the stiffness of molecular bonds. Our preliminary analysis suggests that participants can sense differences between buckminsterfullerene molecules with different bond stiffness parameters and that this limit may fall within the chemically relevant range. Our results highlight how iMD-VR may facilitate a more embodied way of exploring complex and dynamic molecular systems, enabling chemists to sense the properties of molecules purely by interacting with them in VR.

Molecular dynamics simulations are a crucial computational tool for researchers to understand and engineer molecular structure and function in areas such as drug discovery, protein engineering, and material design. Despite their utility, MD simulations are expensive, owing to the high dimensionality of molecular systems. Interactive molecular dynamics in virtual reality (iMD-VR) has recently been developed as a 'human-in-the-loop' strategy, which leverages high-performance computing to accelerate the researcher's ability to solve the hyperdimensional sampling problem. By providing an immersive 3D environment that enables visualization and manipulation of real-time molecular motion, iMD-VR enables researchers and students to efficiently and intuitively explore and navigate these complex, high-dimensional systems. iMD-VR platforms offer a unique opportunity to quickly generate rich datasets that capture human experts' spatial insight regarding molecular structure and function. This paper explores the possibility of employing user-generated iMD-VR datasets to train AI agents via imitation learning (IL). IL is an important technique in robotics that enables agents to mimic complex behaviors from expert demonstrations, thus circumventing the need for explicit programming or intricate reward design. We review the utilization of IL for manipulation tasks in robotics and discuss how iMD-VR recordings could be used to train IL models for solving specific molecular 'tasks'. We then investigate how such approaches could be applied to the data captured from iMD-VR recordings. Finally, we outline the future research directions and potential challenges of using AI agents to augment human expertise to efficiently navigate conformational spaces, highlighting how this approach could provide valuable insight across domains such as materials science, protein engineering, and computer-aided drug design.

Near-death experiences (NDEs) and psychedelic drug experiences (YDEs) enable access to dimensions of non-ordinary sensation, perception, and insight beyond typical day-to-day phenomenology. Both are associated with a dissolution of conventional spatio-temporal conceptual distinctions, and a corresponding sense of connectedness and unity. Moreover, NDEs and YDEs have shown a remarkable ability to reduce the anxiety that people associate with death. In two recent papers, we showed that multi-person virtual reality experiences (VREs) designed within the ‘numadelic’ aesthetic (where bodies are represented as light energy rather than material objects) can elicit psychometric results comparable to YDEs. It nevertheless remains an open question why numadelic aesthetics achieve the observed results, especially given that the vast majority of VREs represent bodies as typically perceived in the ‘real-world’. This article describes the origins of the numadelic aesthetic from subjective accounts of NDE phenomenology, and attempts to unravel mechanistic aspects of the numadelic aesthetic by embedding it within a more general theoretical framework. Specifically, we elaborate a 2-axis schematic grounded in predictive coding models of cognition and matter-energy ideas from physics. One axis tracks ‘structural specificity’, and the other tracks ‘symbolic rigidity’. The majority of VREs, which emphasize photorealistic fidelity to content derived from ‘day-to-day’ phenomenology, are characterized by high structural specificity and high symbolic rigidity. Such approaches collapse imaginative potential into a limited low-entropy space of ‘exogenous’ possibility, unlike the high-entropy brain states associated with YDEs. In contrast, aesthetic domains characterized by low structural specificity and low symbolic rigidity are less concerned with fidelity to phenomenological priors, offering an expansive, ‘uncollapsed’ high-entropy possibility space into which participants can project meaning and corresponding endogenous insights can arise (e.g., as occurs in NDEs and YDEs). Situated within this theoretical framing, the numadelic aesthetic emerges as a practical example of an un-collapsed approach to representation, helping to explain the experimental observations within previous papers. Moreover, the theoretical framing suggests various experimental tests, and lays the groundwork for applying numadelic aesthetics to model NDEs, to help address the anxiety often associated with death.

We describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art ‘human-in-the-loop’ iMD-VR framework to generate a diverse range of protein–ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FE methods. To investigate the performance of the method, we apply iMD-VR-FE to investigate the unbinding of a benzamidine ligand from a trypsin protein. The binding free energy calculated using iMD-VR-FE is similar for each pathway, indicating internal consistency. Moreover, the resulting free energy profiles can distinguish energetic differences between pathways corresponding to various protein–ligand conformations (e.g., helping to identify pathways that are more favourable) and enable identification of metastable states along the pathways. The two-step iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses for candidate pathways in biomolecular systems, quickly obtaining both qualitative and quantitative insight.

Interactive molecular dynamics simulation in virtual reality (iMD-VR) is emerging as a promising technique in molecular science. Here, we demonstrate its use in a range of fifteen applications in materials science and heterogeneous catalysis. In this work, the iMD-VR package Narupa is used with the MD package, DL_POLY [1]. We show how iMD-VR can be used to: (i) investigate the mechanism of lithium fast ion conduction by directing the formation of defects showing that vacancy transport is favoured over interstitialcy mechanisms, and (ii) guide a molecule through a zeolite pore to explore diffusion within zeolites, examining in detail the motion of methyl n-hexanoate in H-ZSM-5 zeolite and identifying bottlenecks restricting diffusion. iMD-VR allows users to manipulate these systems intuitively, to drive changes in them and observe the resulting changes in structure and dynamics. We make these simulations available, as a resource for both teaching and research. All simulation files, with videos, can be found online (https://doi.org/10.5281/zenodo.8252314) and are provided as open-source material.

Introduction: : The potential of virtual reality (VR) to contribute to drug design and development has been recognised for many years. Hardware and software developments now mean that this potential is beginning to be realised, and VR methods are being actively used in this sphere. A recent advance is to use VR not only to visualise and interact with molecular structures, but also to interact with molecular dynamics simulations 'on the fly' (interactive molecular dynamics in VR, IMD-VR), which is useful not only for flexible docking but also to examine binding processes and conformational changes. IMD-VR has been shown to be useful for creating complexes of ligands bound to target proteins, e.g., recently applied to predict binding modes of designed peptide inhibitors of the SARS-CoV-2 main protease. Areas covered: : In this review, the authors use the term 'interactive VR' to refer to software where interactivity is an inherent part of the user VR experience e.g., in making structural modifications or interacting with a physically rigorous molecular dynamics (MD) simulation, as opposed to simply using VR controllers to rotate and translate the molecule for enhanced visualisation. Here, they describe these methods and their application to problems relevant to drug discovery, highlighting the possibilities that they offer in this arena. Expert opinion: : The ease of viewing and manipulating molecular structures and dynamics, using powerful, accessible VR hardware, and the ability to modify structures on the fly (e.g., adding or deleting atoms) - and for groups of researchers to work together in the same virtual environment - makes modern interactive VR a valuable tool to add to the armoury of drug design and development methods.