Developing accurate and efficient coarse-grained representations of proteins is crucial for understanding their folding, function, and interactions over extended timescales. Our methodology involves simulating proteins with molecular dynamics and utilizing the resulting trajectories to train a neural network potential through differentiable trajectory reweighting. Remarkably, this method requires only the native conformation of proteins, eliminating the need for labeled data derived from extensive simulations or memory-intensive end-to-end differentiable simulations. Once trained, the model can be employed to run parallel molecular dynamics simulations and sample folding events for proteins both within and beyond the training distribution, showcasing its extrapolation capabilities. By applying Markov State Models, native-like conformations of the simulated proteins can be predicted from the coarse-grained simulations. Owing to its theoretical transferability and ability to use solely experimental static structures as training data, we anticipate that this approach will prove advantageous for developing new protein force fields and further advancing the study of protein dynamics, folding, and interactions.
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Phosphorylation is central to numerous fundamental cellular processes, influencing the onset and progression of a variety of diseases. The correct identification of these phosphorylation sites is of great importance to unravel the intricate molecular mechanisms within cells and during viral infections, potentially leading to the discovery of new therapeutic targets. In this study, we introduce PTransIPs, a novel deep learning model for the identification of phosphorylation sites. PTransIPs treat amino acids within protein sequences as words, extracting unique encodings based on their type and sequential position. The model also incorporates embeddings from large pretrained protein models as additional data inputs. PTransIPS is further trained on a combination model of convolutional neural network with residual connections and Transformer model equipped with multi-head attention mechanisms. At last, the model outputs classification results through a fully connected layer. The results of independent testing reveal that PTransIPs outperforms existing state-of-the-art(SOTA) methods, achieving AUROCs of 0.9232 and 0.9660 for identifying phosphorylated S/T and Y sites respectively. In addition, ablation studies prove that pretrained model embeddings contribute to the performance of PTransIPs. Furthermore, PTransIPs has interpretable amino acid preference, visible training process and shows generalizability on other bioactivity classification tasks. To facilitate usage, our code and data are publicly accessible at \url{//github.com/StatXzy7/PTransIPs}.
This paper studies the fusogenicity of cationic liposomes in relation to their surface distribution of cationic lipids and utilizes membrane phase separation to control this surface distribution. It is found that concentrating the cationic lipids into small surface patches on liposomes, through phase-separation, can enhance liposome's fusogenicity. Further concentrating these lipids into smaller patches on the surface of liposomes led to an increased level of fusogenicity. These experimental findings are supported by numerical simulations using a mathematical model for phase-separated charged liposomes. Findings of this study may be used for design and development of highly fusogenic liposomes with minimal level of toxicity.
Local modifications of a computational domain are often performed in order to simplify the meshing process and to reduce computational costs and memory requirements. However, removing geometrical features of a domain often introduces a non-negligible error in the solution of a differential problem in which it is defined. In this work, we extend the results from [1] by studying the case of domains containing an arbitrary number of distinct Neumann features, and by performing an analysis on Poisson's, linear elasticity, and Stokes' equations. We introduce a simple, computationally cheap, reliable, and efficient a posteriori estimator of the geometrical defeaturing error. Moreover, we also introduce a geometric refinement strategy that accounts for the defeaturing error: Starting from a fully defeatured geometry, the algorithm determines at each iteration step which features need to be added to the geometrical model to reduce the defeaturing error. These important features are then added to the (partially) defeatured geometrical model at the next iteration, until the solution attains a prescribed accuracy. A wide range of two- and three-dimensional numerical experiments are finally reported to illustrate this work.
We discuss applications of exact structures and relative homological algebra to the study of invariants of multiparameter persistence modules. This paper is mostly expository, but does contain a pair of novel results. Over finite posets, classical arguments about the relative projective modules of an exact structure make use of Auslander-Reiten theory. One of our results establishes a new adjunction which allows us to "lift" these arguments to certain infinite posets over which Auslander-Reiten theory is not available. We give several examples of this lifting, in particular highlighting the non-existence and existence of resolutions by upsets when working with finitely presentable representations of the plane and of the closure of the positive quadrant, respectively. We then restrict our attention to finite posets. In this setting, we discuss the relationship between the global dimension of an exact structure and the representation dimension of the incidence algebra of the poset. We conclude with our second novel contribution. This is an explicit description of the irreducible morphisms between relative projective modules for several exact structures which have appeared previously in the literature.
We propose a generalization of nonlinear stability of numerical one-step integrators to Riemannian manifolds in the spirit of Butcher's notion of B-stability. Taking inspiration from Simpson-Porco and Bullo, we introduce non-expansive systems on such manifolds and define B-stability of integrators. In this first exposition, we provide concrete results for a geodesic version of the Implicit Euler (GIE) scheme. We prove that the GIE method is B-stable on Riemannian manifolds with non-positive sectional curvature. We show through numerical examples that the GIE method is expansive when applied to a certain non-expansive vector field on the 2-sphere, and that the GIE method does not necessarily possess a unique solution for large enough step sizes. Finally, we derive a new improved global error estimate for general Lie group integrators.
Uniform error estimates of a bi-fidelity method for a kinetic-fluid coupled model with random initial inputs in the fine particle regime are proved in this paper. Such a model is a system coupling the incompressible Navier-Stokes equations to the Vlasov-Fokker-Planck equations for a mixture of the flows with distinct particle sizes. The main analytic tool is the hypocoercivity analysis for the multi-phase Navier-Stokes-Vlasov-Fokker-Planck system with uncertainties, considering solutions in a perturbative setting near the global equilibrium. This allows us to obtain the error estimates in both kinetic and hydrodynamic regimes.
Long-span bridges are subjected to a multitude of dynamic excitations during their lifespan. To account for their effects on the structural system, several load models are used during design to simulate the conditions the structure is likely to experience. These models are based on different simplifying assumptions and are generally guided by parameters that are stochastically identified from measurement data, making their outputs inherently uncertain. This paper presents a probabilistic physics-informed machine-learning framework based on Gaussian process regression for reconstructing dynamic forces based on measured deflections, velocities, or accelerations. The model can work with incomplete and contaminated data and offers a natural regularization approach to account for noise in the measurement system. An application of the developed framework is given by an aerodynamic analysis of the Great Belt East Bridge. The aerodynamic response is calculated numerically based on the quasi-steady model, and the underlying forces are reconstructed using sparse and noisy measurements. Results indicate a good agreement between the applied and the predicted dynamic load and can be extended to calculate global responses and the resulting internal forces. Uses of the developed framework include validation of design models and assumptions, as well as prognosis of responses to assist in damage detection and structural health monitoring.
Confidence intervals based on the central limit theorem (CLT) are a cornerstone of classical statistics. Despite being only asymptotically valid, they are ubiquitous because they permit statistical inference under very weak assumptions, and can often be applied to problems even when nonasymptotic inference is impossible. This paper introduces time-uniform analogues of such asymptotic confidence intervals. To elaborate, our methods take the form of confidence sequences (CS) -- sequences of confidence intervals that are uniformly valid over time. CSs provide valid inference at arbitrary stopping times, incurring no penalties for "peeking" at the data, unlike classical confidence intervals which require the sample size to be fixed in advance. Existing CSs in the literature are nonasymptotic, and hence do not enjoy the aforementioned broad applicability of asymptotic confidence intervals. Our work bridges the gap by giving a definition for "asymptotic CSs", and deriving a universal asymptotic CS that requires only weak CLT-like assumptions. While the CLT approximates the distribution of a sample average by that of a Gaussian at a fixed sample size, we use strong invariance principles (stemming from the seminal 1960s work of Strassen and improvements by Koml\'os, Major, and Tusn\'ady) to uniformly approximate the entire sample average process by an implicit Gaussian process. As an illustration of our theory, we derive asymptotic CSs for the average treatment effect using efficient estimators in observational studies (for which no nonasymptotic bounds can exist even in the fixed-time regime) as well as randomized experiments, enabling causal inference that can be continuously monitored and adaptively stopped.
The prediction of protein 3D structure from amino acid sequence is a computational grand challenge in biophysics, and plays a key role in robust protein structure prediction algorithms, from drug discovery to genome interpretation. The advent of AI models, such as AlphaFold, is revolutionizing applications that depend on robust protein structure prediction algorithms. To maximize the impact, and ease the usability, of these novel AI tools we introduce APACE, AlphaFold2 and advanced computing as a service, a novel computational framework that effectively handles this AI model and its TB-size database to conduct accelerated protein structure prediction analyses in modern supercomputing environments. We deployed APACE in the Delta supercomputer, and quantified its performance for accurate protein structure predictions using four exemplar proteins: 6AWO, 6OAN, 7MEZ, and 6D6U. Using up to 200 ensembles, distributed across 50 nodes in Delta, equivalent to 200 A100 NVIDIA GPUs, we found that APACE is up to two orders of magnitude faster than off-the-shelf AlphaFold2 implementations, reducing time-to-solution from weeks to minutes. This computational approach may be readily linked with robotics laboratories to automate and accelerate scientific discovery.
We hypothesize that due to the greedy nature of learning in multi-modal deep neural networks, these models tend to rely on just one modality while under-fitting the other modalities. Such behavior is counter-intuitive and hurts the models' generalization, as we observe empirically. To estimate the model's dependence on each modality, we compute the gain on the accuracy when the model has access to it in addition to another modality. We refer to this gain as the conditional utilization rate. In the experiments, we consistently observe an imbalance in conditional utilization rates between modalities, across multiple tasks and architectures. Since conditional utilization rate cannot be computed efficiently during training, we introduce a proxy for it based on the pace at which the model learns from each modality, which we refer to as the conditional learning speed. We propose an algorithm to balance the conditional learning speeds between modalities during training and demonstrate that it indeed addresses the issue of greedy learning. The proposed algorithm improves the model's generalization on three datasets: Colored MNIST, Princeton ModelNet40, and NVIDIA Dynamic Hand Gesture.
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