Molecular Dynamics Simulations Are Redefining Our View of Peptides Interacting with Biological Membranes

Ever since the first molecular mechanics computer simulations of biological molecules became possible, there has been the dream to study all complex biological phenomena in silico, simply bypassing the enormous experimental challenges and their associated costs. For this, two inherent requirements need to be met: First, the time scales achievable in simulations must reach up to the millisecond range and even longer. Second, the computational model must accurately reproduce what is measured experimentally. Despite some recent successes, the general consensus in the field to date has been that neither of these conditions have yet been met and that the dream will be realized, if at all, only in the distant future. In this Account, we show that this view is wrong; instead, we are actually in the middle of the in silico molecular dynamics (MD) revolution, which is reshaping how we think about protein function. The example explored in this Account is a recent advance in the field of membrane-active peptides (MAPs). MD simulations have succeeded in accurately capturing the process of peptide binding, folding, and partitioning into lipid bilayers as well as revealing how channels form spontaneously from polypeptide fragments and conduct ionic and other cargo across membranes, all at atomic resolution. These game-changing advances have been made possible by a combination of steadily advancing computational power, more efficient algorithms and techniques, clever accelerated sampling schemes, and thorough experimental verifications. The great advantage of MD is the spatial and temporal resolution, directly providing a molecular movie of a protein undergoing folding and cycling through a functional process. This is especially important for proteins with transitory functional states, such as pore-forming MAPs. Recent successes are demonstrated here for the large class of antimicrobial peptides (AMPs). These short peptides are an essential part of the nonadaptive immune system for many organisms, ubiquitous in nature, and of particular interest to the pharmaceutical industry in the age of rising bacterial resistance to conventional antibiotic treatments. Unlike integral membrane proteins, AMPs are sufficiently small to allow converged sampling with the unbiased high-temperature sampling methodology outlined here and are relatively easy to handle experimentally. At the same time, AMPs exhibit a wealth of complex and poorly understood interactions with lipid bilayers, which allow not only tuning and validation of the simulation methodology but also advancement of our knowledge of protein-lipid interactions at a fundamental level. Space constraints limit our discussion to AMPs, but the MD methodologies outlined here can be applied to all phenomena involving peptides in membranes, including cell-penetrating peptides, signaling peptides, viral channel forming peptides, and fusion peptides, as well as ab initio membrane protein folding and assembly. For these systems, the promise of MD simulations to predict the structure of channels and to provide complete-atomic-detail trajectories of the mechanistic processes underlying their biological functions appears to rapidly become a reality. The current challenge is to design joint experimental and computational benchmarks to verify and tune MD force fields. With this, MD will finally fulfill its promise to become an inexpensive, powerful, and easy-to-use tool providing atomic-detail insights to researchers as part of their investigations into membrane biophysics and beyond.