Recent advances in protein conformation sampling by combining machine learning with molecular simulation

The rapid advancement and broad application of machine learning(ML)have driven a groundbreaking revolution in computational biology.One of the most cutting-edge and important applications of ML is its integration with molecular simulations to improve the sampling efficiency of the vast conformational space of large biomolecules.This review focuses on recent studies that utilize ML-based techniques in the exploration of protein conformational landscape.We first highlight the recent development of ML-aided enhanced sampling methods,including heuristic algorithms and neural networks that are designed to refine the selection of reaction coordinates for the construction of bias potential,or facilitate the exploration of the unsampled region of the energy landscape.Further,we review the development of autoencoder based methods that combine molecular simulations and deep learning to expand the search for protein conformations.Lastly,we discuss the cutting-edge methodologies for the one-shot generation of protein conformations with precise Boltzmann weights.Collectively,this review demonstrates the promising potential of machine learning in revolutionizing our insight into the complex conformational ensembles of proteins.

Protein Conformational Change Based on a Two-dimensional Generalized Langevin Equation

A two-dimensional generalized Langevin equation is proposed to describe the protein conformational change, compatible to the electron transfer process governed by atomic packing density model. We assume a fractional Gaussian noise and a white noise through bond and through space coordinates respectively, and introduce the coupling effect coming from both fluctuations and equilibrium variances. The general expressions for autocorrelation functions of distance fluctuation and fluorescence lifetime variation are derived, based on which the exact conformational change dynamics can be evaluated with the aid of numerical Laplace inversion technique. We explicitly elaborate the short time and long time approximations. The relationship between the two-diraensional description and the one-dimensional theory is also discussed.

A Quantum State Scenario for Biological Self-Replication

With the prevalent conception of self-replication (SR, a hallmark of living systems) as a non-equilibrium process subject to thermodynamic laws, a complementary approach derives the low energy quantum states arising from a Hamiltonian that appears to be specific for bio-systems by its containing some strongly binding terms. The bindings attract properties of the template (T) and the reactants to form a replicate (R). The criterion for SR that emerges from the theory is that second order (bi-linear) interaction terms between degrees of motion of T-R and the thermal bath dominate negatively over a linear self-energy term, and thereby provide a binding between the attributes of T and R. The formalism (reminiscent of the Kramers-Anderson mechanism for superexchange) is from first principles, but hinges on a drastic simplification by modelling the T, R and bath variables on interacting qubits and by congesting the attraction into a single (control) parameter. The development relies on further simplifying features, such as Random Phase Approximations and an Effective Hamiltonian formalism. The entropic balance to replication is considered and found to reside in the far surroundings.

Dynamic photoelectrical regulation of ECM protein and cellular behaviors

Dynamic regulation of cell-extracellular matrix(ECM)-material interactions is crucial for various biomedical applications.In this study,a light-activated molecular switch for the modulation of cell attachment/detachment behaviors was established on monolayer graphene(Gr)/n-type Silicon substrates(Gr/Si).Initiated by light illumination at the Gr/Si interface,pre-adsorbed proteins(bovine serum albumin,ECM proteins collagen-1,and fibronectin)underwent protonation to achieve negative charge transfer to Gr films(n-doping)throughπ-πinteractions.This n-doping process stimulated the conformational switches of ECM proteins.The structural alterations in these ECM interactors significantly reduced the specificity of the cell surface receptor-ligand interaction(e.g.,integrin recognition),leading to dynamic regulation of cell adhesion and eventual cell detachment.RNA-sequencing results revealed that the detached bone marrow mesenchymal stromal cell sheets from the Gr/Si system manifested regulated immunoregulatory properties and enhanced osteogenic differentiation,implying their potential application in bone tissue regeneration.This work not only provides a fast and feasible method for controllable cells/cell sheets harvesting but also gives new insights into the understanding of cell-ECM-material communications.

Nanotopographic micro-nano forces finely tune the conformation of macrophage mechanosensitive membrane protein integrinβ_(2)to manipulate inflammatory responses

Finely tuning mechanosensitive membrane proteins holds great potential in precisely controlling inflammatory responses.In addition to macroscopic force,mechanosensitive membrane proteins are reported to be sensitive to micro-nano forces.Integrinβ_(2),for example,might undergo a piconewton scale stretching force in the activation state.High-aspect-ratio nanotopographic structures were found to generate nN-scale biomechanical force.Together with the advantages of uniform and precisely tunable structural parameters,it is fascinating to develop low-aspect-ratio nanotopographic structures to generate micro-nano forces for finely modulating their conformations and the subsequent mechanoimmiune responses.In this study,low-aspect-ratio nanotopographic structures were developed to finely manipulate the conformation of integrinβ_(2).The direct interaction of forces and the model molecule integrinαXβ_(2)was first performed.It was demonstrated that pressing force could successfully induce conformational compression and deactivation of integrinαXβ_(2),and approximately 270 to 720 pN may be required to inhibit its conformational extension and activation.Three low-aspect-ratio nanotopographic surfaces(nanohemispheres,nanorods,and nanoholes)with various structural parameters were specially designed to generate the micro-nano forces.It was found that the nanorods and nanohemispheres surfaces induce greater contact pressure at the contact interface between macrophages and nanotopographic structures,particularly after cell adhesion.These higher contact pressures successfully inhibited the conformational extension and activation of integrinβ_(2),suppressing focal adhesion activity and the downstream PI3K-Akt signaling pathway,reducing NF-κB signaling and macrophage inflammatory responses.Our findings suggest that nanotopographic structures can be used to finely tune mechanosensitive membrane protein conformation changes,providing an effective strategy for precisely modulating inflammatory responses.

Subfunctionalization of a monolignol to a phytoalexin glucosyltransferase is accompanied by substrate inhibition

Uridine diphosphate-dependent glycosyltransferases(UGTs)mediate the glycosylation of plant metabolites,thereby altering their physicochemical properties and bioactivities.Plants possess numerous UGT genes,with the encoded enzymes often glycosylating multiple substrates and some exhibiting substrate inhibition kinetics,but the biological function and molecular basis of these phenomena are not fully understood.The promiscuous monolignol/phytoalexin glycosyltransferase NbUGT72AY1 exhibits substrate inhibition(Ki)at 4 mM scopoletin,whereas the highly homologous monolignol StUGT72AY2 is inhibited at 190 mM.We therefore used hydrogen/deuterium exchange mass spectrometry and structure-based mutational analyses of both proteins and introduced NbUGT72AY1 residues into StUGT72AY2 and vice versa to study promiscuity and substrate inhibition of UGTs.A single F87I and chimeric mutant of NbUGT72AY1 showed significantly reducedscopoletin substrate inhibition,whereas its monolignolgly cosylation activity was almost unaffected.Reverse mutations in StUGT72AY2 resulted in increased scopoletin glycosylation,leading to enhanced promiscuity,which was accompanied by substrate inhibition.Studies of 3D structures identified open and closed UGT conformers,allowing visualization of the dynamics of conformational changes that occur during catalysis.Previously postulated substrate access tunnels likely serve as drainage channels.The results suggest a two-site model in which the second substrate molecule binds near the catalytic site and blocks product release.Mutational studies showed that minor changes in amino acid sequence can enhance the promiscuity of the enzyme and add new capabilities such as substrate inhibition without affecting existing functions.The proposed subfunctionalization mechanism of expanded promiscuity may play a role in enzyme evolution and highlights the importance of promiscuous enzymes in providing new functions.

Effect of succinic acid deamidation-induced modification on wheat gluten

The effect of succinic acid deamidationinduced modification on wheat gluten was investigated in the present study.The changes of surface hydrophobicity,functional properties,secondary structure,and sensibility of proteolysis of modified samples were determined.The solubility of deamidated proteins increased in the isoelectric region of untreated wheat gluten.The isoelectric point of succinic acid deamidated wheat gluten was shifted to a basic pH and existed in the broad pH regions.Foaming property and molecular flexibility of wheat gluten were improved after the modification.The hydrolysis degree of the hydrolysates in proteolysis with flavorzyme and pancreatin increased after succinic acid deamidation.Moreover,succinic acid deamidation-induced modification resulted in little change in molecular weight and secondary structure of the protein.Thus,succinic acid could facilitate unfolding protein conformation.In addition,it could improve protein-water interactions,surface properties,and sensibility of the proteolysis of the deamidated wheat gluten.

Fibrinogen Adsorption on Biomaterials as Characterized by Transmission FTIR Spectroscopy

The adsorption of plasma proteins onto biomaterials can be characterized by either the amount of adsorbed protein or the conformation of the adsorbed proteins. The adsorption characteristics of biomaterials are important for hemocompatibility evaluation. In this investigation, the amount of adsorbed human fibrinogen (HFG) and the conformation of the adsorbed HFG on different surfaces were measured simultaneously using transmission FTIR. The surface materials included CaF 2, polymethyl methacrylate (PMMA), type II polyurethane made by Chengdu University of Science & Technology, pellethane 2363 55D and pellethane 2363 80A. The results indicate that both the amount of adsorbed protein and the conformation of the adsorbed protein can be measured simultaneously using a single transmission FTIR technique. The result also suggests that a single parameter, either the adsorbed amount or the conformation of the adsorbed HFG, can not provide complete information about the hemocompatibility of the biomaterials.