Making the Undruggable Druggable: Molecular Simulation as Computational Microscopy for Target Detection in Disordered and Liquid-Like Assemblies
Introduction
In this poster, I will present a glimpse into intrinsically disordered and liquid-like biological assemblies as next-generation grand challenges in cancer drug design. I will show you how modern computer simulation tools can be useful in identifying druggable targets in intrinsically disordered and liquid-like assemblies. Computer simulations give us a precise spatiotemporal picture of the system beyond an ensemble average, which enables us to access every single conformer that makes an ensemble at given conditions.
Methods
In this work, we developed and benchmarked a molecular simulation technique that will enable us to identify druggable targets in intrinsically disordered and liquid-like assemblies. Computer simulations give us a precise spatiotemporal picture of the system beyond an ensemble average, which enables us access to every single conformer that makes an ensemble at given conditions. Molecular dynamics (MD) simulations at atomic resolution could, in principle, monitor molecular interactions with a high accuracy; however, their high computational costs still preclude their widespread use for simulating LLPS. Coarse-grained (CG) simulations using a reduced representation enable direct simulations of phase behavior and can give a good description of effective molecular interactions. Among the CG models, the MARTINI force field offers a resolution that preserves molecular details with an explicit (CG) solvent while being able to achieve condensate formation in a reasonable computing time. Single-molecule (sm) properties have been commonly used as objective functions for force field optimization. One of the most commonly used parameters to tune for such force field optimizations is the protein-water interaction strength. This parameter has been used for the optimization of the MARTINI force field. Inspired by the success of the work for sm properties, we tested a range of scaled protein-water interactions for condensate formation. We refer to the scaling parameter as 𝜆; the parameter with which we multiply the ε of the LJ interactions between protein and water beads. We presented the results where the 𝜆 parameter varies between 1-1.04.
Results
While the unmodified MARTINI force field yields a complete collapse of proteins into one dense phase (i.e., no dilute phase), we reported a range of modified protein–water interaction strength that is capable of capturing the experimentally found transfer free energy between dense and dilute phases. We also found that the condensates lose their spherical shape upon the addition of salt, especially when the protein–water interactions are weak. Interchain amino acid contact map analysis showed one explanation for this observation: the protein–protein contact fraction reduces as salt is added to systems (when the protein–water interactions are weak), consistent with electrostatic screening effects. This reduction might be responsible for the condensates becoming nonspherical upon the addition of salt by reducing the need for minimizing the interfacial area. However, as the protein–water interactions become stronger to the extent that makes the transfer free energy agree well with experimentally observed transfer free energy, we found an increase in the protein–protein contact fraction upon the addition of salt, consistent with the salting-out effects.
Conclusion
We had three major conclusions: 1) there is an intricate balance between screening effects and salting-out effects upon the addition of salt and this balance is highly sensitive to the strength of protein–water interactions, 2) parameters that give good agreement for single-molecule properties do not work for condensate formation, 3) adding salt doesn’t change this though it possibly has an interesting effect on morphology.