In this paper, we introduce multiscale persistent functions for biomolecular structure characterization. The essential idea is to combine our multiscale rigidity functions with persistent homology analysis, so as to construct a series of multiscale persistent functions, particularly multiscale persistent entropies, for structure characterization. To clarify the fundamental idea of our method, the multiscale persistent entropy model is discussed in great detail. Mathematically, unlike the previous persistent entropy or topological entropy, a special resolution parameter is incorporated into our model. Various scales can be achieved by tuning its value. Physically, our multiscale persistent entropy can be used in conformation entropy evaluation. More specifically, it is found that our method incorporates in it a natural classification scheme. This is achieved through a density filtration of a multiscale rigidity function built from bond and/or dihedral angle distributions. To further validate our model, a systematical comparison with the traditional entropy evaluation model is done. It is found that our model is able to preserve the intrinsic topological features of biomolecular data much better than traditional approaches, particularly for resolutions in the mediate range. Moreover, our method can be successfully used in protein classification. For a test database with around nine hundred proteins, a clear separation between all-alpha and all-beta proteins can be achieved, using only the dihedral and pseudo-bond angle information. Finally, a special protein structure index (PSI) is proposed, for the first time, to describe the "regularity" of protein structures. Essentially, PSI can be used to describe the "regularity" information in any systems.

Principal component analysis (PCA) is arguably the most widely used dimension-reduction method for vector-type data. When applied to a sample of images, PCA requires vectorization of the image data, which in turn entails solving an eigenvalue problem for the sample covariance matrix. We propose herein a two-stage dimension reduction (2SDR) method for image reconstruction from high-dimensional noisy image data. The first stage treats the image as a matrix, which is a tensor of order 2, and uses multilinear principal component analysis (MPCA) for matrix rank reduction and image denoising. The second stage vectorizes the reduced-rank matrix and achieves further dimension and noise reduction. Simulation studies demonstrate excellent performance of 2SDR, for which we also develop an asymptotic theory that establishes consistency of its rank selection. Applications to cryo-EM (cryogenic electronic microscopy), which has revolutionized structural biology, organic and medical chemistry, cellular and molecular physiology in the past decade, are also provided and illustrated with benchmark cryo-EM datasets. Connections to other contemporaneous developments in image reconstruction and high-dimensional statistical inference are also discussed.

Ligand-receptor binding and unbinding are fundamental biomolecular processes and particularly essential to drug efficacy. Environmental water fluctuations, however, impact the corresponding thermodynamics and kinetics and thereby challenge theoretical descriptions. Here, we devise a holistic, implicit-solvent, multi-method approach to predict the (un)binding kinetics for a generic ligand-pocket model. We use the variational implicit-solvent model (VISM) to calculate the solute-solvent interfacial structures and the corresponding free energies, and combine the VISM with the string method to obtain the minimum energy paths and transition states between the various metastable (“dry” and “wet”) hydration states. The resulting dry-wet transition rates are then used in a spatially-dependent multi-state continuous-time Markov chain Brownian dynamics simulations, and the related Fokker–Planck equation calculations, of the ligand stochastic motion, providing the mean first-passage times for binding and unbinding. We find the hydration transitions to significantly slow down the binding process, in semi-quantitative agreement with existing explicit-water simulations, but significantly accelerate the unbinding process. Moreover, our methods allow the characterization of non-equilibrium hydration states of pocket and ligand during the ligand movement, for which we find substantial memory and hysteresis effects for binding versus unbinding. Our study thus provides a significant step forward towards efficient, physics-based interpretation and predictions of the complex kinetics in realistic ligand-receptor systems.

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Let $(V, 0)$ be an isolated hypersurface singularity defined by the holomorphic function $f: (\mathbb{C}^n, 0)\rightarrow (\mathbb{C}, 0)$. In our previous work, we introduced a series of novel Lie algebras associated to $(V,0)$, i.e., $k$-th Yau algebra $L^k(V), k\geq 0$. It was defined to be the Lie algebra of derivations of the $k$-th moduli algebras $A^k(V)= \mathcal{O}_n/(f, m^k J(f)), k\geq 0$, where $m$ is the maximal ideal of $\mathcal{O}_n$. I.e., $L^k(V):=\text{Der}(A^k(V), A^k(V))$. The dimension of $L^k(V)$ was denoted by $\lambda^k(V)$. The number $\lambda^k(V)$, which was called $k$-th Yau number, is a subtle numerical analytic invariant of $(V, 0)$. Furthermore, we formulated two conjectures for these $k$-th Yau number invariants: a sharp upper estimate conjecture of $\lambda^k(V)$ for weighted homogeneous isolated hypersurface singularities (see Conjecture \ref{conj2}) and an inequality conjecture $\lambda^{(k+1)}(V) > \lambda^k(V), k\geq0$ (see Conjecture \ref{conj1}). In this article, we verify these two conjectures when $k$ is small for large class of singularities.