Molecular dynamics (MD) simulations are capable of reproducing dynamic evolution at the molecular scale, but are limited by temporal scales. Enhanced sampling has emerged as a powerful tool to improve sampling efficiency, thereby extending the simulation timescales of a range of simulation studies in materials, chemistry, biology, nanoscience, and related fields. Here, we provide a systematic overview of established enhanced sampling methods and clarify the principles and interconnections between these methods. Furthermore, we categorically elaborate on the state-of-the-art applications of enhanced sampling in the last five years. Through these exemplified applications, we discuss the unique advantages of this technique, showing the prospects and challenges for its future development. This review could help researchers in different fields gain a comprehensive understanding of the enhanced sampling technique, and jointly facilitate its application and advancement.

Controlling the cellular interaction and internalization of polymer-modified nanoparticles (NPs) is of central importance to the development of promising nanomedicines. Here, we describe the use of synthetic polypeptides for NP surface coating and regulation of their cellular uptake behaviors by simply switching the conformation and anchoring orientation. Our results show that gold NPs (AuNPs) coated with a helical poly(γ-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)esteryl _L-glutamate) (_L-P(EG₃Glu)₅₀) from the C-terminus ((L-C)-AuNPs) exhibit greater zeta potential and more cellular uptake (2.0–5.5 fold higher) than those coated with the same polypeptide but anchored from the N-terminus ((L-N)-AuNPs), or from both the C- and N-terminus at a 1/1 molar ratio ((L-C/L-N)-AuNPs). A similar orientation-regulated cellular internalization pattern is observed in _D-P(EG₃Glu)₅₀ but not the unstructured _DL-P(EG₃Glu)₅₀-modified AuNPs, suggesting an important and universal role of the helix-derived macrodipole in cellular uptake. Moreover, this orientation-governed internalization is successfully reproduced in P(EG₃Glu)₅₀-coated gold nanorods (AuNRs), and applied to the design of doxorubicin-loaded polypeptide micelles. Simulation study offers time-resolved insights regarding the NP–membrane interactions and membrane remodeling. Thus, our study provides a delicate way of regulating the surface chemistry of NPs and the subsequent NP–cell interactions. Moreover, the results highlight the uniqueness of polypeptides in NP surface engineering, and urge a more careful consideration on the polymer orientation effect.