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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., (© 2023. Springer Nature Limited.)

With a growing body of research highlighting the therapeutic potential of experiential phenomenology which diminishes egoic identity and increases one's sense of connectedness, there is significant interest in how to elicit such 'self-transcendent experiences' (STEs) in laboratory contexts. Psychedelic drugs (YDs) have proven particularly effective in this respect, producing subjective phenomenology which reliably elicits intense STEs. With virtual reality (VR) emerging as a powerful tool for constructing new perceptual environments, we describe a VR framework called 'Isness-distributed' (Isness-D) which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. Within Isness-D, groups of participants co-habit a shared virtual space, collectively experiencing their bodies as luminous energetic essences with diffuse spatial boundaries. It enables moments of 'energetic coalescence', a new class of embodied intersubjective experience where bodies can fluidly merge, enabling participants to include multiple others within their self-representation. To evaluate Isness-D, we adopted a citizen science approach, coordinating an international network of Isness-D 'nodes'. We analyzed the results (N = 58) using 4 different self-report scales previously applied to analyze subjective YD phenomenology (the inclusion of community in self scale, ego-dissolution inventory, communitas scale, and the MEQ30 mystical experience questionnaire). Despite the complexities associated with a distributed experiment like this, the Isness-D scores on all 4 scales were statistically indistinguishable from recently published YD studies, demonstrating that distributed VR can be used to design intersubjective STEs where people dissolve their sense of self in the connection to others., (© 2022. The Author(s).)