Commentary and Perspective (Invited)
GENESIS and CHARMM-GUI: Advances and applications from Hands-on training program C at RIKEN
2024 Volume 21 Issue Supplemental2 Article ID: e212008
Details
2024 Volume 21 Issue Supplemental2 Article ID: e212008
My recent participation in the IUPAB2024 CHARMM-GUI/GENESIS Workshop provided me with an extensive and immersive experience in advanced molecular dynamics (MD) simulations. This workshop, held from June 30 to July 2, 2024, featured sessions on various topics, including molecular dynamics theories, enzyme mechanisms, membrane biology, and cellular component modeling. The hands-on training sessions were particularly enlightening, allowing me to apply theoretical knowledge in a practical setting. This commentary and perspective highlight my hands-on training experience, focusing on the insights gained, the challenges faced, and the potential applications of the techniques learned. During the workshop, two main aspects of the training were covered: the GENESIS software [1–3] and supercomputer Fugaku from RIKEN Center for Computational Science (Figure 1) and the CHARMM-GUI software [4] from Lehigh University (Figure 2). More detailed information about the meeting and workshop can be found at https://cbp.riken.jp/meeting/workshop/iupab2024-genesis-workshop/.
The workshop commenced with sessions devoted to molecular dynamics principles and strategies. Noteworthy presentations included Helmut Grubmüller’s discussion on constant pH simulations with Fast Multipole Methods (FMM) and solvation shell entropies, as well as Kei Moritsugu’s insights into weighted ensemble methods for biomolecules. These sessions provided a strong theoretical foundation for comprehending the subsequent hands-on activities.
Enzyme MechanismsThe second session focused on enzyme mechanisms, featuring advancements in multiscale QM/MM and free simulation methods for enzyme modeling presented by Kwangho Nam. Youngmin Rhee’s talk on non-adiabatic dynamics in following photodynamics in biology was particularly informative, emphasizing the dynamic nature of enzyme interactions.
Hands-on GENESIS: Part 1The hands-on sessions began with an introduction to GENESIS, led by Chigusa Kobayashi and assisted by a team of teaching assistants. We started with the basics of GENESIS and its implementation on the supercomputer Fugaku (Figure 3). This session provided a comprehensive overview of GENESIS’s capabilities and its application in high-performance computational environments. Utilizing Fugaku, the world’s most powerful supercomputer, was a remarkable experience. Fugaku’s immense computational power enabled the simulation of intricate biomolecular systems with unprecedented accuracy and speed. This hands-on experience highlighted the potential of leveraging cutting-edge technology for advanced molecular dynamics simulations. This experience has proven to be invaluable for me as one of the Malaysian students joined this. This experience would have been impossible for me to have in my home country. The use of this technology has truly captivated me and has amplified my enthusiasm for engaging in research partnerships with RIKEN.
The afternoon session transitioned to CHARMM-GUI, introduced by Wonpil Im. We explored the Membrane Builder module, a tool for constructing membrane models essential for simulating membrane proteins. The hands-on component allowed us to create and manipulate membrane systems, providing a practical understanding of the CHARMM-GUI interface.
The second day commenced with presentations on membrane biology. Chen Song’s talk on the gating mechanism of the mechanosensitive ion channel NOMPC using molecular dynamics simulations shed new light on membrane protein function. Jana Shen’s discussion on drug-membrane partitioning and crossing emphasized the significance of unbiased molecular dynamics coupled with proton titration. I am particularly interested in Jana Shen’s work because it is related to the field of drug design, which is a part of my research project.
Modeling of Cellular Components: Part IThe focus then shifted to modeling cellular components. Presentations by Jianhan Chen and Michael Feig on coarse-grained simulations and multi-scale modeling of biomolecular condensates, respectively, underscored the importance of integrating different simulation scales for a comprehensive understanding of cellular processes. The coarse-grained simulations and multi-scale modeling are new to me, and learning about them gives me a new perspective on molecular dynamic simulation. The coarse-grained technique also gives me ideas for its application in drug design development.
Hands-on GENESIS: Part 2The afternoon session featured advanced hands-on training with GENESIS. Cheng Tan led a session on coarse-grained simulations, followed by Jaewoon Jung’s lecture on high-performance computation. These sessions emphasized the versatility of GENESIS in handling large-scale simulations and the practical skills required to optimize computational workflows. The experience of running simulations on Fugaku was particularly noteworthy. The ability to execute high-performance computations efficiently opened new avenues for exploring complex biomolecular dynamics, far surpassing the capabilities available in many developing countries like Malaysia, where access to such advanced computational resources is limited.
Hands-on CHARMM-GUI: Part 2The CHARMM-GUI training continued with Nathan Kern’s introduction to the multi-component assembler. This module is crucial for constructing complex biomolecular systems. The hands-on component allowed us to assemble multi-component systems, providing a deeper understanding of CHARMM-GUI’s capabilities.
The final day of the program commenced with sessions focused on integrating molecular dynamics simulations with experimental data. The presentations by Gerhard Hummer on integrating simulations and experiments, and Naoto Hori on coarse-grained simulations of RNA folding, provided valuable perspectives on combining computational and experimental approaches.
Hands-on GENESIS: Part 3The hands-on training with GENESIS concluded with a session on generalized-ensemble simulations, led by Shingo Ito. This session covered advanced simulation techniques, enhancing our ability to explore a wide range of biomolecular states. Learning about the generalized ensemble method and replica exchange methods was a highlight. These techniques are crucial for efficiently sampling the conformational space of biomolecules, and overcoming the limitations of traditional MD simulations. The practical experience with these methods was transformative, providing new tools to address complex biochemical questions.
Hands-on CHARMM-GUI: Part 3The final CHARMM-GUI session, led by Donghyuk Suh, introduced the enhanced sampler module. This tool is essential for sampling biomolecular conformations efficiently. The hands-on activity allowed us to apply the enhanced sampling techniques, solidifying our understanding of CHARMM-GUI’s advanced features.
Note: The sessions discussed in this report represent a selection of the talks delivered during the workshop. Other presentations not mentioned here contributed equally to the overall learning experience.
The workshop was an enriching experience that offered a comprehensive exploration of molecular dynamics and enzyme mechanisms. The seamless integration of theoretical knowledge with practical, hands-on training using advanced tools and resources was particularly beneficial. As a Malaysian student, this opportunity was invaluable, providing exposure to technologies and methodologies not readily available in my home country. This experience has inspired me to pursue further research collaborations with institutions like RIKEN and has equipped me with the skills necessary to contribute to innovative research in computational chemistry and molecular biology.
I was especially impressed by the structure and schedule of the program. The combination of research presentations by leading experts, lecture sessions, and hands-on activities provided a deep understanding of the subject matter. The hands-on sessions were crucial in bridging the gap between theory and practice. Working directly with GENESIS and CHARMM-GUI allowed me to apply the theoretical concepts discussed in the lectures, significantly deepening my understanding of molecular dynamics simulations.
The interesting aspect of GENESIS [1,2] a product of RIKEN, lies in its versatility and extensive compatibility with various operating systems, including Linux, Mac OS X, and Windows, as well as support for multiple Fortran and C compilers, such as GCC, Intel, Fujitsu, and Cygwin/Mingw. Optimized for high-performance hardware, such as Intel® Xeon®, AMD EPYC™, ARM processors, and NVIDIA GPUs, GENESIS can efficiently execute on top supercomputers like Fugaku, Flow, TSUBAME 3.0, Cygnus, and Oakbridge-CX. This broad compatibility and robust performance make GENESIS an indispensable tool for researchers worldwide, particularly those with limited access to advanced computational resources. It allows them to conduct cutting-edge research in molecular dynamics and computational chemistry [1–3].
GENESIS’s integration of generalized-ensemble and coarse-grained models presents a transformative approach to molecular dynamics simulations [3]. The generalized-ensemble model, which combines conventional molecular dynamics and enhanced sampling techniques, offers a sophisticated solution for overcoming the limitations of traditional simulations. By incorporating methods such as simulated tempering, temperature replica exchange, umbrella sampling, and metadynamics, this model enables a more comprehensive exploration of the conformational space of biomolecules.
The coarse-grained models available in GENESIS, such as AICG2+ for proteins, 3PSC.N for double-stranded DNA, PWMcos for protein-DNA interactions, and HPS for FUS condensation, provide a powerful means to study large biomolecular systems at reduced computational cost [5]. These models allow for the simplification of complex systems while retaining essential biological details, enabling the investigation of larger systems and longer timescales than would be feasible with all-atom simulations [6].
The sampling methods employed in GENESIS, such as gREST, gREST/REUS, and the string method, represent potent resources for the investigation of intricate biological systems. gREST has been utilized to explore the S-protein present on the surface of CoV-19 [7], while gREST/REUS offers comprehensive insights into kinase-inhibitor binding [8]. The string method investigates conformational shifts in Ca2+-ATPase [9]. These strategies facilitate the precise capture of biomolecular dynamics, thereby enhancing our comprehension of molecular mechanisms and interactions in a diverse array of biological contexts.
Utilizing GENESIS from RIKEN (Figure 4), which is optimized for high-performance computing environments like the supercomputer Fugaku, I can leverage these advanced models to conduct simulations with unprecedented accuracy and efficiency [6]. The ability to apply generalized-ensemble and coarse-grained models within this robust software framework opens new avenues for my research, enabling me to tackle complex biochemical questions and develop innovative solutions [10]. This experience not only enhances my understanding of molecular dynamics but also equips me with cutting-edge tools and methodologies to push the boundaries of computational chemistry and molecular biology.
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In the workshop, the CHARMM Graphical User Interface (GUI) was also introduced as a universally accessible platform for molecular modeling and simulations [11]. This platform caters to both novice and expert users in the field of computational chemistry, providing a robust and versatile environment. The CHARMM-GUI achieves this by seamlessly integrating advanced molecular dynamics tools with an intuitive interface [12].
The open-source nature of the CHARMM-GUI allows for continuous enhancements and customization, empowering users to tailor simulations to their specific research needs. In the context of GENESIS, the CHARMM-GUI is an indispensable tool for exploring the dynamics and interactions of biomolecular systems. It supports studies ranging from protein folding to molecular assembly processes, enabling researchers to delve into complex biological phenomena.
The CHARMM-GUI’s applications extend to guiding rational drug design initiatives, utilizing detailed molecular insights to advance biophysical research and therapeutic development. This powerful tool contributes significantly to the field by providing detailed molecular insights essential for progressing biophysical research and therapeutic development.
One of the key obstacles encountered during the workshop was optimizing simulation parameters for a variety of biomolecular systems. The guidance of instructors and teaching assistants was invaluable in overcoming these difficulties, emphasizing the importance of expert support in mastering complex simulation techniques.
The techniques acquired during the workshop have numerous potential applications in my research. The capacity to conduct high-performance simulations with GENESIS and construct intricate biomolecular systems with CHARMM-GUI will strengthen my research capabilities, particularly in exploring enzyme mechanisms and membrane protein dynamics. As a student from Malaysia, a developing country, this experience was particularly impactful. It provided exposure to cutting-edge computational tools and methods that are not yet fully available in my home country’s research infrastructure. The knowledge obtained from this workshop will be crucial in advancing MD simulation research in Malaysia.
Enhancing the IUPAB 2024 GENESIS Workshop could involve extending the duration of hands-on sessions, especially for the CHARMM-GUI module, as the current timeframe might not allow for thorough exploration. Incorporating detailed case studies and practical examples would help participants apply concepts more independently. Furthermore, improving the preparation of teaching materials, similar to the well-organized GENESIS session, would enhance comprehension. The well-structured plan and schedule have already contributed to the workshop’s success. Following the event, it would benefit organizers and trainers to maintain contact with attendees, encouraging continued learning and collaboration.
Future organizers might also consider adapting the content to various skill levels by providing preparatory materials or separate tracks for beginners and advanced participants. This approach would help maintain engagement across a diverse audience. Additionally, incorporating more interactive, problem-based learning activities, such as collaborative projects utilizing GENESIS and CHARMM-GUI, could strengthen the workshop’s hands-on component. Offering continued post-workshop support, such as online Q&A sessions or a resource repository, would further extend the learning experience and assist participants in applying what they have learned. Finally, broadening the workshop’s global reach by offering virtual sessions or recorded materials could make it more accessible to a larger audience. Future workshops could enhance their impact and relevance within the scientific community by addressing these areas.
Finally, I would like to suggest the organizer prepare certificates for participants who completed the Program C (GENESIS and CHARMM-GUI) training at RIKEN during the IUPAB Congress 2024, formally recognizing their successful participation and completion of the program. Additionally, it would be beneficial to include a special acknowledgment for those who received the training grant, highlighting their achievement in being selected for the grant and emphasizing the support provided for their professional development.
The IUPAB2024 GENESIS/CHARMM-GUI Workshop provided an extensive and immersive training experience in molecular dynamics simulations. The hands-on sessions were especially beneficial, offering practical skills that complement theoretical knowledge. The insights acquired from this workshop will undoubtedly contribute to my future research endeavors, allowing me to conduct more sophisticated and precise simulations of biomolecular systems. The opportunity to use Fugaku and GENESIS, along with learning advanced methods like generalized-ensemble and replica exchange simulations, has significantly broadened my perspectives and equipped me with the tools to extend the boundaries of MD simulation research.
Thank you for giving me the opportunity to attend and train in Program C (GENESIS and CHARMM-GUI) at RIKEN during the IUPAB Congress 2024. I am also sincerely grateful for being selected to receive the training grant. This experience has profoundly impacted my studies and career development, and I deeply appreciate your support.
Other than that, we would like to thank the University of Malaya for the financial support provided through the Impact-Oriented Interdisciplinary Research Grant Programme (Grant No. IIRG001B-2021FNW).
