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This journal publishes original research papers of reasonable permanent intellectual value, in the areas of computer modeling in engineering & Sciences, including, but not limited to computational mechanics, computational materials, computational mathematics, computational physics, computational chemistry, and computational biology, pertinent to solids, fluids, gases, biomaterials, and other continua spanning from various spatial length scales (quantum, nano, micro, meso, and macro), and various time scales (picoseconds to hours) are of interest. Papers which deal with multi-physics problems, as well as those which deal with the interfaces of mechanics, chemistry, and biology, are particularly encouraged. Novel computational approaches and state-of-the-art computation algorithms, such as soft computing, artificial intelligence-based machine learning methods, and computational statistical methods are welcome.
Recursive Scale Comp 1.06 for After Effects
The effects of somatic mutations that transform polyspecific germline (GL) antibodies to affinity mature (AM) antibodies with monospecificity are compared among three GL-AM Fab pairs. In particular, changes in conformational flexibility are assessed using a Distance Constraint Model (DCM). We have previously established that the DCM can be robustly applied across a series of antibody fragments (VL to Fab), and subsequently, the DCM was combined with molecular dynamics (MD) simulations to similarly characterize five thermostabilizing scFv mutants. The DCM is an ensemble based statistical mechanical approach that accounts for enthalpy/entropy compensation due to network rigidity, which has been quite successful in elucidating conformational flexibility and Quantitative Stability/Flexibility Relationships (QSFR) in proteins. Applied to three disparate antibody systems changes in QSFR quantities indicate that the VH domain is typically rigidified, whereas the VL domain and CDR L2 loop become more flexible during affinity maturation. The increase in CDR H3 loop rigidity is consistent with other studies in the literature. The redistribution of conformational flexibility is largely controlled by nonspecific changes in the H-bond network, although certain Arg to Asp salt bridges create highly localized rigidity increases. Taken together, these results reveal an intricate flexibility/rigidity response that accompanies affinity maturation.
There is much evidence to suggest that mature antibodies, especially within the CDRs, are inherently more rigid than their GL precursors. Lipovsek et al.  demonstrated that constricting the flexibility of CDRs with inter-loop disulfide bonds enhanced the affinity of immunoglobulin interactions. Schmidt et al.  studied a broadly neutralizing influenza virus antibody using long-scale molecular dynamics and demonstrated that maturation rigidifies the initially flexible heavy-chain CDRs, which accounts for most of the affinity gain. Jorg et al.  applied three-pulse photon echo spectroscopy and molecular dynamic to explore the flexibility of mature 4-4-20 antibody and found that the binding site of the mature antibody is significantly rigidified compared to that of the GL, and that the increased rigidity occurs via increased coupling within and between CDR loops and the antibody framework. Finally, Manivel et al.  proposed that more unfavorable entropy changes are associated with ligand binding within GL antibodies compared to AM.
In this report, we similarly characterize the effects of somatic mutations on the flexibility/rigidity changes by analyzing three GL-AM antigen-binding fragment (Fab) pairs. Interestingly, CDR H3 loop is rigidified after affinity maturation in all three cases. We observe a rich mixture of increased rigidity and flexibility along the backbone, and many of these changes are significantly long-ranged. In many instances specific hydrogen bonds or salt bridges that form in regions where there is tight side chain packing play an important role in rigidifying CDRs during the maturation process. The accompanying loss of conformational entropy due to this increase in rigidity near the mutation site is an enthalpy-entropy compensation mechanism that the DCM captures well through network rigidity. In addition, molecular couplings that describe flexibility and rigidity correlations between residues are frequently enhanced by somatic mutations. The structural plasticity of GL antibodies and associated trends in how rigidity and flexibility profiles redistribute upon maturation likely represent general mechanisms used by the immune response and could be used to guide design high affinity and selective antibodies for desired function.
Lastly, there is a critically important step that must be executed when determining if a constraint is independent or redundant. When the PG is used to calculate whether a constraint is independent or redundant during a recursive process of building the PG graph one constraint at a time , the constraints are placed in preferential order from lowest to highest component entropies. With this preferential ordering, the calculation of conformational entropy provides a lowest possible upper bound estimate. Conceptually, total conformational entropy reflects the minimal set of the most constrictive yet independent interactions. Solvation free energy contributions are modeled by the phenomenological usol and vnat parameters  that are conjugate to the intramolecular H-bonds and packing order parameters respectively. While mutations are known to quantitatively affect solvation free energies , the same usol and vnat parameters are used throughout because the changes are not expected to be large here due to the overall structural similarity across the dataset. 041b061a72