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Abstract BACKGROUNDThe strongest genetic drivers of late‐onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2^R47H. Despite their critical roles, the mechanisms underlying their interactions remain poorly understood. METHODSWe conducted microsecond‐long molecular dynamics simulations of TREM2‐ApoE complexes, including TREM2^R47H, validating our findings through comparison with published experimental data on TREM2‐ApoE binding interactions. RESULTSOur simulations reveal TREM2^WTcan sample an “open” CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2^WTexhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2^R47H’s CDR2 may explain its reduced ligand‐binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2‐ApoE2 complexes, which is absent with ApoE4. TREM2^R47Hand ApoE4 mutually rigidify each other, suppressing interfacial flexibility. DISCUSSIONOur findings suggest mechanisms underlying ApoE2's neuroprotective functions, ApoE4's pathogenicity, and the synergistic effects of ApoE4 and TREM2^R47Hin AD. TREM2^WT’s flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2^R47H‐ApoE4 interactions may drive pathogenic signaling. HighlightsTREM2^WTsamples diverse CDR2 conformations, challenging prior assumptions that an “open” CDR2 state is solely pathogenic.ApoE2 promotes dynamic reconfiguration of TREM2‐ApoE2 complexes, preserving TREM2^WT's flexibility.ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding.The TREM2^R47H‐ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility. 

Abstract Polymeric micro‐ and nanoparticles are useful vehicles for delivering cytokines to diseased tissues such as solid tumors. Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid–liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine‐delivery systems, a clear molecular understanding of the interactions between relevant proteins and solvents used in the preparation of such particles is needed. We utilized an integrated computational and experimental approach for studying the governing mechanisms by which interleukin‐12 (IL‐12), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic‐aqueous solvent interface formed during double emulsification. We investigated protein–protein interactions between human (h)IL‐12 and albumin and simulated these components in pure water, dichloromethane (DCM), and along a water/DCM interface to replicate the solvent regimes formed during double emulsification. We observed that (i) hIL‐12 experiences increased structural deviations near the water/DCM interface, and (ii) hIL‐12 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL‐12 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL‐12 and sufficient time is allowed for albumin‐hIL‐12 binding. Findings from this work have implications in establishing design principles to enhance the stability of cytokines and other unstable proteins in particles formed by double emulsification for improved stability and therapeutic efficacy. 

Unaltered biological matter (biomatter) can be harnessed to fabricate cohesive, sustainable bioplastics. However, controlling the material properties of these bioplastics is challenging, as the contributions of different macromolecular building blocks to processability and performance are unknown. To deconvolute the roles of different classes of biomolecules, we developed experimental and computational methods to construct and analyze biomatter analogs composed of carbohydrates, proteins, and lipids. These analogs are intended to improve fundamental understanding of biomatter plastics. Spectroscopic analyses of biomatter analogs suggest that cohesion depends on protein aggregation during thermomechanical processing. Molecular dynamics simulations confirm that alterations to protein conformation and hydrogen bonding are likely the primary mechanisms underlying the formation of a cohesive, proteinaceous matrix. Simulations also corroborate experimental measurements highlighting the importance of hydrogen bonding and self-assembly between specific, small-molecule constituents. These conclusions may enable the engineering of next-generation biomatter plastics with improved performance. 

Abstract The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer’s disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in stabilizing the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the ‘Expanded Surface 2’, which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding in the presence of R47H. This suggests that sTREM2’s neuroprotective role in AD may, at least in part, arise from the stalk domain’s ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in membrane-bound TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD. 

Abstract Biological organisms experience constantly changing environments, from sudden changes in physiology brought about by feeding, to the regular rising and setting of the Sun, to ecological changes over evolutionary timescales. Living organisms have evolved to thrive in this changing world but the general principles by which organisms shape and are shaped by time varying environments remain elusive. Our understanding is particularly poor in the intermediate regime with no separation of timescales, where the environment changes on the same timescale as the physiological or evolutionary response. Experiments to systematically characterize the response to dynamic environments are challenging since such environments are inherently high dimensional. This roadmap deals with the unique role played by time varying environments in biological phenomena across scales, from physiology to evolution, seeking to emphasize the commonalities and the challenges faced in this emerging area of research.